Heterocyclic prolinamide derivatives

ABSTRACT

This invention is directed to novel heterocyclic prolinamide derivatives of Formula I,and pharmaceutically acceptable salts, solvates, solvates of the salt and prodrugs thereof, useful in the prevention (e.g., delaying the onset of or reducing the risk of developing) and treatment (e.g., controlling, alleviating, or slowing the progression of) of age-related macular degeneration (AMD) and related diseases of the eye. These diseases include dry-AMD, wet-AMD, geographic atrophy, diabetic retinopathy, retinopathy of prematurity, polypoidal choroidal vasculopathy, and degeneration of retinal or photoreceptor cells. The invention disclosed herein is further directed to methods of prevention, slowing the progress of, and treatment of dry-AMD, wet-AMD, and geographic atrophy, diabetic retinopathy, retinopathy of prematurity, polypoidal choroidal vasculopathy, and degeneration of retinal or photoreceptor cells, comprising: administration of a therapeutically effective amount of compound of the invention. The compounds of the invention are inhibitors of HTRA1. Thus, the compounds of the invention are useful in the prevention and treatment of a wide range of diseases mediated (in whole or in part) by HTRA1. The compounds of the invention are also useful for inhibiting HTRA1 protease activity in an eye or locus of an arthritis or related condition.

BACKGROUND OF THE INVENTION Field of the Invention

The present disclosure is directed to novel heterocyclic prolinamide derivatives, pharmaceutical compositions containing such novel compounds, as well as methods for preventing and treating age-related macular degeneration (AMD) and related diseases of the eye.

Description of the Related Art

Age-related macular degeneration (AMD) is the leading cause of severe loss of vision in people over the age of 60. Age is the major risk factor for the onset of AMD: the likelihood of developing AMD triples after age 55. Many factors, however, contribute to the likelihood that an individual will develop AMD.

As summarized in WO2001/006262, “environmental” conditions may modulate the rate at which an individual develops AMD or the severity of the disease. Light exposure has been proposed as a possible risk factor, since AMD most severely affects the macula, where light exposure is high. (See Young, R. W. (1988), Surv. Ophthalmol. 32(4), 252-69; Taylor, H. R. et al., (1990), Trans. Amer. Ophthalmol. Soc. 88, 163-73; Schalch W. (1992), Exs, 62, 280-98). The amount of time spent outdoors is associated with increased risk of choroidal neovascularization in men, and wearing hats and/or sunglasses is associated with a decreased incidence of soft drusen (Cruickshanks, K. et al., (1993), Arch. Ophthalmol., 111, 514-518). Accidental exposure to microwave irradiation has also been shown to be associated with the development of numerous drusen (Lim, J. et al., (1993), Retina. 13, 230-3). Cataract removal and light iris pigmentation has also been reported as a risk factor in some studies (Sandberg, M. et al., (1994), Invest. Ophthalmol. Vis. Sci. 35(6), 2734-40). This suggests that: 1) eyes prone to cataracts may be more likely to develop AMD; 2) the surgical stress of cataract removal may result in increased risk of AMD, due to inflammation or other surgically-induced factors; or 3) cataracts prevent excessive light exposure from falling on the macula, and are in some way prophylactic for AMD. While it is possible that dark iris pigmentation may protect the macula from light damage, it is difficult to distinguish between iris pigmentation alone and other, co-segregating genetic factors which may be actual risk factors.

Smoking, gender (women are at greater risk), obesity, and repeated exposure to UV radiation also increase the risk of AMD.

More recently, a number of HTRA1 single nucleotide polymorphs (SNP) have been found to be associated with an increased risk of AMD. See, for example, WO2008/013893A2, WO2008/067040A2 and WO2008/094370A2. These SNP's include rs11200638, rs10490924, rs3750848, rs3793917 and rs932275. In particular, the risk allele rs11200638, was found to be associated with increased HTRA1 mRNA and protein expression, and HTRA1 is present in drusen in patients with AMD. (See Dewan et al., (2006), Science 314:989-992; Yang et al., (2006), Science 314:992-993). These disclosures provide evidence that HTRA1 is an important factor in AMD and the progression thereof.

In broad terms, there are two forms of AMD: dry AMD and wet AMD. The dry form is the more common, and accounts for 85-90% of the patients with AMD, and does not typically result in blindness. In dry AMD, (also called non-neovascular AMD or non-exudative AMD) drusen appear in the macula of the eye, the cells in the macula die, and vision becomes blurry. Dry AMD can progress in three stages: 1) early, 2) intermediate, and 3) advanced dry AMD. Dry AMD can also progress into wet AMD during any of these stages.

Wet AMD (also called neovascular or exudative AMD), is associated with pathologic posterior segment neovascularization. The posterior segment neovascularization (PSNV) found in exudative AMD is characterized as pathologic choroidal neovascularization. Leakage from abnormal blood vessels forming in this process damages the macula and impairs vision, eventually leading to blindness.

The end stage of AMD is characterized by a complete degeneration of the neurosensory retina and of the underlying retinal pigment epithelium in the macular area. Advanced stages of AMD can be subdivided into geographic atrophy (GA) and exudative AMD. Geographic atrophy is characterized by progressive atrophy of the retinal pigment epithelium (RPE). While GA is typically considered less severe than the exudative AMD because its onset is less sudden, to date no treatment has been effective at halting or slowing its progression.

Currently, treatment of dry AMD includes the administration of antioxidant vitamins and/or zinc. For example, one study at the National Eye Institute assessed a composition comprising vitamin C, β-carotene, zinc oxide and cupric oxide.

Treatment of wet AMD is also wanting. Available drug therapies include: bevacizumab (Avastin®, Genentech, CA), ranibizumab (Lucentis®, Genentech, CA), pegaptanib (Macugen® Bausch & Lomb, NJ), and aflibercept (Eylea®, Regeneron, NY). In each instance, the medication is injected into the eye. Injections may be repeated every four to eight weeks to maintain the beneficial effect of the medication. Those with a positive result may partially recover vision as the blood vessels shrink and the fluid under the retina is absorbed, allowing retinal cells to regain some function.

Pharmacologic therapy for the treatment of macular edema associated with AMD is lacking. The current standard of care is laser photocoagulation, which is used to stabilize or resolve macular edema and retard the progression to later stage disease. Laser photocoagulation may reduce retinal ischemia by destroying healthy tissue and thereby decreasing metabolic demand; it also may modulate the expression and production of various cytokine and trophic factors. There are no current treatments for preventing loss of vision after dry AMD enters an advanced stage. There are also no definitive methods for preventing progression of dry AMD to an advanced stage, other than by avoiding and/or reducing risk factors and using dietary supplements, which cannot guarantee or be relied on to stop AMD progression. Thus, there is a need for therapeutics that can treat dry AMD and prevent progression of dry to wet AMD.

The compound (1-{3-cyclohexyl-2-[naphthalene-2-carbonyl)-amino]-propionyl}-pyrrolidine-2-carboxylic acid [5-(3-cyclohexyl-ureido)-1-dihydroxyboranyl-pentyl]-amide is disclosed in Grau, S. et. al., (2006), J. Biol. Chem., 281(10):6124-6129 and in WO2012/078540 (identified therein as NVP-LB976) as an inhibitor of HTRA1.

In addition to AMD, a number of publications have described a potential role of HTRA1 and disease, including retinal angiomatous proliferation (Ohkuma, Y., et al., (2014) Clin. Ophthalmol., 8:143-8), foveomacular proliferation (Chowers, I., et al., (2015) Progress in Retinal and Eye Research, 47:64-85), musculoskeletal diseases, including osteoarthritis, spinal disk degeneration rheumatoid arthritis, muscular dystrophy and osteoporosis (Taiden, A. N. and Richards, P. J. (2013) Am. J. Pathology, 182(5):1482-8), and treatment of autologous chondrocytes prior to intraarticular implantation (Ollitrault, D. et al., (2015) Tissue Engineering, Part C Methods, 21(2):133-47). An HTRA1 inhibitor thus may demonstrate a therapeutic benefit in these additional indications.

SUMMARY OF THE INVENTION

The present disclosure is directed to novel heterocyclic prolinamide derivatives of Formula I, and pharmaceutically acceptable salts, solvates, solvates of the salts and prodrugs thereof, pharmaceutical compositions comprising a compound of Formula I, as well as methods for preventing and treating age-related macular degeneration (AMD) and related diseases of the eye comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula I. These diseases include, but are not limited to, dry-AMD, wet-AMD, geographic atrophy, diabetic retinopathy, retinopathy of prematurity, polypoidal choroidal vasculopathy, and degeneration of retinal or photoreceptor cells. The compounds of the present disclosure are inhibitors of HTRA1, and are useful in the prevention and treatment of diseases mediated (in whole or in part) by HTRA1. The compounds of the present disclosure are also useful for inhibiting HTRA1 protease activity in an eye or locus of an arthritis or related condition.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

In a first embodiment aspect the present disclosure provides compounds of Formula (I):

or a pharmaceutically acceptable salt, solvate, solvate of the salt or prodrug thereof wherein: W is selected from the group consisting of: —B(OH)₂ and —C(O)C(O)NR⁷R⁸; X is selected from the group consisting of: —O—, —S(O)_(p)— and —N(C(O)OR⁶)—; Y is selected from the group consisting of: —C(O)—, —SO₂—, and —NHC(O)—; R¹ is selected from the group consisting of:

-   -   (a) —(CH₂)₀₋₆-aryl,     -   (b) —(CH₂)₀₋₆-heteroaryl,     -   (c) —(CH₂)₀₋₆—C₃₋₈cycloalkyl optionally substituted with phenyl,         and     -   (d) —(CH₂)₀₋₆-heterocyclyl optionally substituted with phenyl or         oxo,         wherein the aryl and heteroaryl of choices (a) and (b) are each         optionally substituted with 1 to 3 substituents independently         selected from the group consisting of:     -   (i) -halogen,     -   (ii) —CN,     -   (iii) —C₁₋₆alkyl,     -   (iv) —C₀₋₆alkyl-R⁵,     -   (v) —C₂₋₆alkenyl,     -   (vi) —C₂₋₆alkynyl,     -   (vii) —C(O)R⁷,     -   (viii) —CO₂R⁷,     -   (ix) —CONR⁷R⁸,     -   (x) —OH,     -   (xi) —O—C₁₋₆alkyl,     -   (xii) —O—C₀₋₆alkyl-R⁵,     -   (xiii) —SH,     -   (xiv) —S(O)_(p)—C₁₋₆alkyl,     -   (xv) —S(O)_(p)—C₀₋₆alkyl-R⁵,     -   (xvi) —S(O)₂NR⁷R⁸,     -   (xvii) —NO₂,     -   (xviii) —NR⁷R⁸,     -   (xix) —NHC(O)R⁷,     -   (xx) —NHC(O)OR⁷,     -   (xxi) —NHC(O)NR⁷R⁸,     -   (xxii) —NHSO₂C₁₋₆alkyl, and     -   (xxiii) —NHSO₂C₀₋₆alkyl-R⁵,         wherein each of the alkyl group of choices (iii), (iv), (xi),         (xii), (xiv), (xv), (xxii) and (xxiii) is optionally substituted         with 1 to 5 substituents independently selected from -halogen,         -haloC₁₋₄alkyl, —COR⁷, —CO₂R⁷, —CONR⁷R⁸, —NR⁷R⁸, —OH,         —O—C₁₋₄alkyl, —SH and —S—C₁₋₄alkyl; R² is selected from the         group consisting of:     -   (a) —C₃₋₈alkyl and     -   (b) —C₀₋₆alkyl-R⁵,         wherein each of the alkyl group of choices (a) and (b) is         optionally substituted with 1 to 5 substituents independently         selected from:     -   (i) -halogen,     -   (ii) -haloC₁₋₄alkyl,     -   (iii) —NR⁷R⁸,     -   (iv) —OH,     -   (v) —O—C₁₋₄alkyl,     -   (vi) —SH,     -   (vii) —S—C₁₋₄alkyl;     -   (viii) —NR⁷SO₂C₁₋₄alkyl, and     -   (ix) —NR⁷C(O)OR⁷,         R^(3a) is H, and R^(3b) is selected from the group consisting         of:     -   (a) —H,     -   (b) —OH,     -   (c) -heteroaryl,     -   (d) —O-heteroaryl,     -   (e) -heterocycle,     -   (f) -aryl, and     -   (g) —O-aryl;         wherein each of the heteroaryl of choices (c) and (d), the         heterocycle of choice (e) and the aryl of choices (f) and (g) is         optionally substituted with 1 to 3 groups independently selected         from the group consisting of:     -   (i) -halogen,     -   (ii) —OH,     -   (iii) —CR¹⁰R¹¹R¹²,     -   (iv) —(CH₂)₀₋₃—NHSO₂—C₁₋₄alkyl,     -   (v) —(CH₂)₀₋₃—SO₂—C₁₋₄alkyl,     -   (vi) —(CH₂)₀₋₃—C(O)O—C₁₋₄alkyl, and     -   (vii) —CN; and         wherein the heterocycle of choice (e) is additionally optionally         substituted with 1 to 2 oxo groups; or         R^(3a) and R^(3b) together represent oxo;         each R⁴ is independently selected from the group consisting of:     -   (a) —C₁₋₄alkyl,     -   (b) -haloC₁₋₄alkyl,     -   (c) —OH,     -   (d) —O—C₁₋₄alkyl,     -   (e) —O-haloC₁₋₄alkyl, and     -   (f) -halogen;         each R⁵ is independently selected from the group consisting of:     -   (a) —C₃₋₁₂cycloalkyl,     -   (b) -aryl,     -   (c) -heteroaryl, and     -   (d) -heterocyclyl,         wherein each of choices (a) to (d) is optionally substituted         with 1 to 3 substituents independently selected from the group         consisting of:     -   (i) —C₁₋₄alkyl,     -   (ii) -halogen,     -   (iii) —NR⁷R⁸,     -   (iv) —OH,     -   (v) —O—C₁₋₄alkyl,     -   (vi) —SH, and     -   (vii) —S—C₁₋₄alkyl;         wherein each of the alkyl group of choices (i), (v) and (vii) is         optionally substituted with 1 to 5 substituents independently         selected from -halogen, -haloC₁₋₄alkyl, —OH, —O—C₁₋₄alkyl, —SH         and —S—C₁₋₄alkyl;         R⁶ is selected from the group consisting of:     -   (a) —C₁₋₆alkyl, and     -   (b) —C₀₋₆alkyl-aryl;         each R⁷ and each R⁸ are independently selected from the group         consisting of:     -   (a) —H,     -   (b) —C₁₋₆alkyl,     -   (c) —C₀₋₆alkyl-C₃₋₁₂cycloalkyl,     -   (d) —C₀₋₆alkyl-heterocyclyl,     -   (e) —C₀₋₆alkyl-heteroaryl,     -   (f) —C₀₋₆alkyl-aryl,     -   (g) —C₂₋₆alkenyl, and     -   (h) —C₂₋₆alkynyl,         wherein the alkyl group of choices (b)-(f), the alkenyl group of         choice (g), the cycloalkyl group of choice (c), and the alkynyl         group of (h) is optionally substituted with 1 to 3 groups         independently selected from:     -   (i) -halogen,     -   (ii) —C₁₋₄alkyl,     -   (iii) —C(O)C₁₋₄alkyl,     -   (iv) —OH,     -   (v) —OC₁₋₄alkyl,     -   (vi) —SH,     -   (vii) —SC₁₋₄alkyl,     -   (viii) —NH₂,     -   (ix) —NH(C₁₋₄alkyl), and     -   (x) —N(C₁₋₄alkyl)(C₁₋₄alkyl); or         R⁷, R⁸ and the nitrogen atom to which they are attached together         form a 3- to 7-membered monocyclic or 6- to 11-membered bicyclic         heterocycle optionally having an additional heteroatom selected         from O, S(O)_(p), and NR⁹, and wherein said heterocycle is         optionally substituted with 1 to 2 groups independently selected         from halogen;         R⁹ is selected from the group consisting of:     -   (a) —H,     -   (b) —C₁₋₄alkyl,     -   (c) —C(O)—C₁₋₄alkyl,     -   (d) —C(O)NH₂,     -   (e) —C(O)—NH(C₁₋₄alkyl),     -   (f) —C(O)—N(C₁₋₄alkyl)₂, and     -   (g) —C(O)O—C₁₋₄alkyl;         R¹⁰, R¹¹, and R¹² are independently selected from the group         consisting of: H, halogen, —OH and —C₁₋₆ alkyl; or         R¹⁰, R¹¹ and the carbon atom to which they are attached together         form a C₃₋₁₂cycloalkyl or a heterocyclyl group;         k is 0, 1, 2, 3 or 4;         n and m are independently selected from 0, 1, 2 and 3, with the         proviso that n+m is 0, 1, 2, 3 or 4; and         p is 0, 1 or 2.

In a second embodiment, for a compound of the first embodiment, R¹ is selected from the group consisting of:

-   -   (a) -aryl, and     -   (b) -heteroaryl,         wherein the aryl and heteroaryl of choices (a) and (b) are each         optionally substituted with 1 to 3 substituents independently         selected from the group consisting of:     -   (i) -halogen,     -   (ii) —CN,     -   (iii) —C₁₋₆alkyl,     -   (iv) —C₀₋₆alkyl-R⁵,     -   (v) —C₂₋₆alkenyl,     -   (vi) —C₂₋₆alkynyl,     -   (vii) —C(O)R⁷,     -   (viii) —CO₂R⁷,     -   (ix) —CONR⁷R⁸,     -   (x) —OH,     -   (xi) —O—C₁₋₆alkyl,     -   (xii) —O—C₀₋₆alkyl-R⁵,     -   (xiii) —SH,     -   (xiv) —S(O)_(p)—C₁₋₆alkyl,     -   (xv) —S(O)_(p)—C₀₋₆alkyl-R⁵,     -   (xvi) —S(O)₂NR⁷R⁸,     -   (xvii) —NO₂,     -   (xviii) —NR⁷R⁸,     -   (xix) —NHC(O)R⁷,     -   (xx) —NHC(O)OR⁷,     -   (xxi) —NHC(O)NR⁷R⁸,     -   (xxii) —NHSO₂C₁₋₆alkyl, and     -   (xxiii) —NHSO₂C₀₋₆alkyl-R⁵,         wherein each of the alkyl group of choices (iii), (iv), (xi),         (xii), (xiv), (xv), (xxii) and (xxiii) is optionally substituted         with 1 to 5 substituents independently selected from -halogen,         -haloC₁₋₄alkyl, —COR⁷, —CO₂R⁷, —CONR⁷R⁸, —NR⁷R⁸, —OH,         —O—C₁₋₄alkyl, —SH and —S—C₁₋₄alkyl.

In a third embodiment, for a compound of any of the preceding embodiments, R^(3b) is selected from the group consisting of:

-   -   (a) —OH,     -   (b) -heteroaryl,     -   (c) —O-heteroaryl,     -   (d) -heterocycle,     -   (e) -aryl, and     -   (f) —O-aryl;         wherein each of the heteroaryl of choices (b) and (c), the         heterocycle of choice (d) and the aryl of choices (e) and (f) is         optionally substituted with 1 to 3 groups independently selected         from the group consisting of:     -   (i) -halogen,     -   (ii) —OH,     -   (iii) —CR¹⁰R¹¹R¹²,     -   (iv) —C₀₋₃alkyl-NHSO₂—C₁₋₄alkyl,     -   (v) —C₀₋₃alkyl-SO₂—C₁₋₄alkyl,     -   (vi) —C₀₋₃alkyl-C(O)O—C₁₋₄alkyl, and     -   (vii) —CN;         wherein the heterocycle of choice (d) is additionally optionally         substituted with 1 to 2 oxo groups; or         R^(3a) and R^(3b) together represent oxo.

In a fourth embodiment, for a compound of any of the preceding embodiments, R^(3b) is selected from the group consisting of:

-   -   (a) —OH,     -   (b) -heteroaryl,     -   (c) —O-heteroaryl, and     -   (d) -heterocycle,         wherein each of the heteroaryl of choices (b) and (c), and the         heterocycle of choice (d) is optionally substituted with 1 to 3         groups independently selected from the group consisting of:     -   (i) -halogen,     -   (ii) —OH,     -   (iii) —CR¹⁰R¹¹R¹²,     -   (iv) —C₀₋₃alkyl-NHSO₂—C₁₋₄alkyl,     -   (v) —C₀₋₃alkyl-SO₂—C₁₋₄alkyl,     -   (vi) —C₀₋₃alkyl-C(O)O—C₁₋₄alkyl, and     -   (vii) —CN;         wherein the heterocycle of choice (d) is additionally optionally         substituted with 1 to 2 oxo groups.

In a fifth embodiment, for a compound of any of the preceding embodiments, R^(3b) is selected from the group consisting of:

-   -   (a) —OH,     -   (b)

-   -   (c) —O-heteroaryl, and     -   (d)

wherein HAr is heteroaryl and Hcyl is heterocycle, and HAr, heteroaryl of choice (c), and Hcyl are each optionally substituted with 1 to 3 groups independently selected from the group consisting of:

-   -   (i) -halogen,     -   (ii) —OH,     -   (iii) —CR¹⁰R¹¹R¹²,     -   (iv) —C₀₋₃alkyl-NHSO₂—C₁₋₄alkyl,     -   (v) —C₀₋₃alkyl-SO₂—C₁₋₄alkyl,     -   (vi) —C₀₋₃alkyl-C(O)O—C₁₋₄alkyl, and     -   (vii) —CN;         wherein Hcyl is additionally optionally substituted with 1 to 2         oxo groups.

In a sixth embodiment, for a compound of any of the preceding embodiments, R^(3b) is selected from the group consisting of:

-   -   (a)

and

-   -   (b)

wherein HAr is heteroaryl and Hcyl is heterocycle, and HAr and Hcyl are each optionally substituted with 1 to 3 groups independently selected from the group consisting of:

-   -   (i) -halogen,     -   (ii) —OH,     -   (iii) —CR¹⁰R¹¹R¹²,     -   (iv) —C₀₋₃alkyl-NHSO₂—C₁₋₄alkyl,     -   (v) —C₀₋₃alkyl-SO₂—C₁₋₄alkyl,     -   (vi) —C₀₋₃alkyl-C(O)O—C₁₋₄alkyl, and     -   (vii) —CN;         wherein Hcyl is additionally optionally substituted with 1 to 2         oxo groups.

In a seventh embodiment, for a compound of any of the preceding embodiments, R² is —C₁₋₆alkyl-R⁵, wherein the alkyl group is optionally substituted with 1 to 3 substituents independently selected from:

-   -   (i) -halogen,     -   (ii) -haloC₁₋₄alkyl,     -   (iii) —O—C₁₋₄alkyl,     -   (iv) —S—C₁₋₄alkyl.

In an eighth embodiment, for a compound of any of the preceding embodiments, R⁵ is —C₃₋₁₂ cycloalkyl optionally substituted with 1 to 3 substituents independently selected from the group consisting of:

-   -   (i) —C₁₋₄alkyl,     -   (ii) -halogen,     -   (iii) —O—C₁₋₄alkyl,     -   (iv) —S—C₁₋₄alkyl;

wherein each of the alkyl group of choices (i), (iii) and (iv) is optionally substituted with 1 to 5 substituents independently selected from -halogen, -haloC₁₋₄alkyl, —OH, —O—C₁₋₄alkyl, —SH and —S—C₁₋₄alkyl;

In a ninth embodiment, for a compound of any of the preceding embodiments, W is —C(O)C(O)NR⁷R⁸.

In a tenth embodiment, for a compound of any of the preceding embodiments, X is —O— or —S(O)_(p)—.

In an eleventh embodiment, the compound of the first embodiment is a compound having the formula (Ia):

or a pharmaceutically acceptable salt, solvate, solvate of the salt or prodrug thereof wherein: W is selected from the group consisting of: —B(OH)₂ and —C(O)C(O)NR⁷R⁸;

X is —O— or —S(O)_(p)—;

Y is selected from the group consisting of: C(O)—, —SO₂—, and —NHC(O)—; R¹ is selected from the group consisting of:

-   -   (a) -aryl,     -   (b) -heteroaryl,         wherein the aryl and heteroaryl of choices (a) and (b) are each         optionally substituted with 1 to 3 substituents independently         selected from the group consisting of:     -   (i) -halogen,     -   (ii) —CN,     -   (iii) —C₁₋₆alkyl,     -   (iv) —C₀₋₆alkyl-R⁵,     -   (v) —C₂₋₆alkenyl,     -   (vi) —C₂₋₆alkynyl,     -   (vii) —C(O)R⁷,     -   (viii) —CO₂R⁷,     -   (ix) —CONR⁷R⁸,     -   (x) —OH,     -   (xi) —O—C₁₋₆alkyl,     -   (xii) —O—C₀₋₆alkyl-R⁵,     -   (xiii) —SH,     -   (xiv) —S(O)_(p)—C₁₋₆alkyl,     -   (xv) —S(O)_(p)—C₀₋₆alkyl-R⁵,     -   (xvi) —S(O)₂NR⁷R⁸,     -   (xvii) —NO₂,     -   (xviii) —NR⁷R⁸,     -   (xix) —NHC(O)R⁷,     -   (xx) —NHC(O)OR⁷,     -   (xxi) —NHC(O)NR⁷R⁸,     -   (xxii) —NHSO₂C₁₋₆alkyl, and     -   (xxiii) —NHSO₂C₀₋₆alkyl-R⁵,         wherein each of the alkyl group of choices (iii), (iv), (xi),         (xii), (xiv), (xv), (xxii) and (xxiii) is optionally substituted         with 1 to 5 substituents independently selected from -halogen,         -haloC₁₋₄alkyl, —COR⁷, —CO₂R⁷, —CONR⁷R⁸, —NR⁷R⁸, —OH,         —O—C₁₋₄alkyl, —SH and —S—C₁₋₄alkyl;         R^(3a) is H and R^(3b) is selected from the group consisting of:     -   (a) —OH,     -   (b) -heteroaryl,     -   (c) —O-heteroaryl,     -   (d) -heterocycle,     -   (e) -aryl, and     -   (f) —O-aryl;         wherein each of the heteroaryl of choices (b) and (c), the         heterocycle of choice (d) and the aryl of choices (e) and (f) is         optionally substituted with 1 to 3 groups independently selected         from the group consisting of:     -   (i) -halogen,     -   (ii) —OH,     -   (iii) —CR¹⁰R¹¹R¹²,     -   (iv) —C₀₋₃alkyl-NHSO₂—C₁₋₄alkyl,     -   (v) —C₀₋₃alkyl-SO₂—C₁₋₄alkyl,     -   (vi) —C₀₋₃alkyl-C(O)O—C₁₋₄alkyl, and     -   (vii) —CN;         wherein the heterocycle of choice (d) is additionally optionally         substituted with 1 to 2 oxo groups; or         R^(3a) and R^(3b) together represent oxo;         R⁴ is selected from the group consisting of:     -   (a) —C₁₋₄alkyl,     -   (b) -haloC₁₋₄alkyl,     -   (c) —OH,     -   (d) —O—C₁₋₄alkyl,     -   (e) —O-haloC₁₋₄alkyl, and     -   (f) -halogen;         R⁵ is —C₃₋₁₂cycloalkyl optionally substituted with 1 to 3         substituents independently selected from the group consisting         of:     -   (i) —C₁₋₄alkyl,     -   (ii) -halogen,     -   (iii) —O—C₁₋₄alkyl,     -   (iv) —S—C₁₋₄alkyl;         wherein each of the alkyl group of choices (i), (iii) and (iv)         is optionally substituted with 1 to 5 substituents independently         selected from -halogen, -haloC₁₋₄alkyl, —OH, —O—C₁₋₄alkyl, —SH         and —S—C₁₋₄alkyl;         each R⁷ and each R⁸ are independently selected from the group         consisting of:     -   (a) —H,     -   (b) —C₁₋₆alkyl,     -   (c) —C₀₋₆alkyl-C₃₋₁₂cycloalkyl,     -   (d) —C₀₋₆alkyl-heterocyclyl,     -   (e) —C₀₋₆alkyl-heteroaryl,     -   (f) —C₀₋₆alkyl-aryl,     -   (g) —C₂₋₆alkenyl, and     -   (h) —C₂₋₆alkynyl,         wherein the alkyl group of choices (b)-(f), the alkenyl group of         choice (g), the cycloalkyl group of choice (c), and the alkynyl         group of (h) is optionally substituted with 1 to 3 groups         independently selected from:     -   (i) -halogen,     -   (ii) —C₁₋₄alkyl,     -   (iii) —C(O)C₁₋₄alkyl,     -   (iv) —OH,     -   (v) —OC₁₋₄alkyl,     -   (vi) —SH,     -   (vii) —SC₁₋₄alkyl,     -   (viii) —NH₂,     -   (ix) —NH(C₁₋₄alkyl), and     -   (x) —N(C₁₋₄alkyl)(C₁₋₄alkyl); or         R⁷, R⁸ and the nitrogen atom to which they are attached together         form a 3- to 7-membered monocyclic or 6- to 11-membered bicyclic         heterocycle optionally having an additional heteroatom selected         from O, S(O)_(p), and NR⁹, and wherein said heterocycle is         optionally substituted with 1 to 2 groups independently selected         from halogen;         R⁹ is selected from the group consisting of:     -   (a) —H,     -   (b) —C₁₋₄alkyl,     -   (c) —C(O)—C₁₋₄alkyl,     -   (d) —C(O)NH₂,     -   (e) —C(O)—NH(C₁₋₄alkyl),     -   (f) —C(O)—N(C₁₋₄alkyl)₂, and     -   (g) —C(O)O—C₁₋₄alkyl;         R¹⁰, R¹¹, and R¹² are independently selected from the group         consisting of: H, halogen, —OH and —C₁₋₆ alkyl; or         R¹⁰, R¹¹ and the atom to which they are attached together form a         C₃₋₁₂cycloalkyl or a heterocyclyl group;         k is 0, 1, 2, 3 or 4;         n and m are independently selected from 0, 1, 2 and 3, with the         proviso that n+m is 0, 1, 2, 3 or 4;         p is 0, 1 or 2.

In a twelfth embodiment, for a compound of the eleventh embodiment having formula (Ia), R^(3b) is selected from the group consisting of:

-   -   (a) —OH,     -   (b)

-   -   (c) —O-heteroaryl, and     -   (d)

wherein HAr is heteroaryl and Hcyl is heterocycle, and HAr, heteroaryl of choice (c), and Hcyl are each optionally substituted with 1 to 3 groups independently selected from the group consisting of:

-   -   (i) -halogen,     -   (ii) —OH,     -   (iii) —CR¹⁰R¹¹R¹²,     -   (iv) —C₀₋₃alkyl-NHSO₂—C₁₋₄alkyl,     -   (v) —C₀₋₃alkyl-SO₂—C₁₋₄alkyl,     -   (vi) —C₀₋₃alkyl-C(O)O—C₁₋₄alkyl, and     -   (vii) —CN;         wherein Hcyl is additionally optionally substituted with 1 to 2         oxo groups.

In a thirteenth embodiment, for a compound having the formula (Ia) of any of the preceding embodiments, R^(3b) is selected from the group consisting of:

-   -   (a)

and

-   -   (b)

wherein HAr is heteroaryl and Hcyl is heterocycle, and HAr and Hcyl are each optionally substituted with 1 to 3 groups independently selected from the group consisting of:

-   -   (i) -halogen,     -   (ii) —OH,     -   (iii) —CR¹⁰R¹¹R¹²,     -   (iv) —C₀₋₃alkyl-NHSO₂—C₁₋₄alkyl,     -   (v) —C₀₋₃alkyl-SO₂—C₁₋₄alkyl,     -   (vi) —C₀₋₃alkyl-C(O)O—C₁₋₄alkyl, and     -   (vii) —CN;         wherein Hcyl is additionally substituted with 1 to 2 oxo groups.

In a fourteenth embodiment, for a compound having the formula (Ia) of any of the preceding embodiments, W is —C(O)C(O)NH₂.

In a fifteenth embodiment, for a compound having the formula (Ia) of any of the preceding embodiments, Y is —C(O)—.

In a sixteenth embodiment, for a compound having the formula (Ia) of any of the preceding embodiments,

W is —C(O)C(O)NH₂; Y is —C(O)—; and

R^(3b) is selected from the group consisting of:

-   -   (a)

and

-   -   (b)

wherein HAr is heteroaryl and Hcyl is heterocycle, and each heteroaryl and heterocycle is optionally substituted with 1 to 3 groups independently selected from the group consisting of:

-   -   (i) -halogen,     -   (ii) —OH,     -   (iii) —C¹⁰R¹¹R¹²,     -   (iv) —C₀₋₃alkyl-NHSO₂—C₁₋₄alkyl,     -   (v) —C₀₋₃alkyl-SO₂—C₁₋₄alkyl,     -   (vi) —C₀₋₃alkyl-C(O)O—C₁₋₄alkyl, and     -   (vii) —CN;         wherein the heterocycle is additionally substituted with 1 to 2         oxo groups

In a seventeenth embodiment, the compound of the first embodiment is a compound having the formula (Ib):

or a pharmaceutically acceptable salt, solvate, solvate of the salt or prodrug thereof, wherein W is selected from the group consisting of: —B(OH)₂ and —C(O)C(O)NR⁷R⁸; X is selected from the group consisting of: —O—, —S(O)_(p)— and —N(C(O)OR⁶)—; Y is selected from the group consisting of: —C(O)—, —SO₂—, and —NHC(O)—; R¹ is selected from the group consisting of:

-   -   (a) -aryl,     -   (b) -heteroaryl,         wherein the aryl and heteroaryl of choices (a) and (b) are each         optionally substituted with 1 to 3 substituents independently         selected from the group consisting of:     -   (i) -halogen,     -   (ii) —CN,     -   (iii) —C₁₋₆alkyl,     -   (iv) —C₀₋₆alkyl-R⁵,     -   (v) —C₂₋₆alkenyl,     -   (vi) —C₂₋₆alkynyl,     -   (vii) —C(O)R⁷,     -   (viii) —CO₂R⁷,     -   (ix) —CONR⁷R⁸,     -   (x) —OH,     -   (xi) —O—C₁₋₆alkyl,     -   (xii) —O—C₀₋₆alkyl-R⁵,     -   (xiii) —SH,     -   (xiv) —S(O)_(p)—C₁₋₆alkyl,     -   (xv) —S(O)_(p)—C₀₋₆alkyl-R⁵,     -   (xvi) —S(O)₂NR⁷R⁸,     -   (xvii) —NO₂,     -   (xviii) —NR⁷R⁸,     -   (xix) —NHC(O)R⁷,     -   (xx) —NHC(O)OR⁷,     -   (xxi) —NHC(O)NR⁷R⁸,     -   (xxii) —NHSO₂C₁₋₆alkyl, and     -   (xxiii) —NHSO₂C₀₋₆alkyl-R⁵,         wherein each of the alkyl group of choices (iii), (iv), (xi),         (xii), (xiv), (xv), (xxii) and (xxiii) is optionally substituted         with 1 to 5 substituents independently selected from -halogen,         -haloC₁₋₄alkyl, —COR⁷, —CO₂R⁷, —CONR⁷R⁸, —NR⁷R⁸, —OH,         —O—C₁₋₄alkyl, —SH and —S—C₁₋₄alkyl;         R² is selected from the group consisting of:     -   (a) —C₃₋₈alkyl and     -   (b) —C₀₋₆alkyl-R⁵,         wherein each of the alkyl group of choices (a) and (b) is         optionally substituted with 1 to 5 substituents independently         selected from:     -   (i) -halogen,     -   (ii) -haloC₁₋₄alkyl,     -   (iii) —NR⁷R⁸,     -   (iv) —OH,     -   (v) —O—C₁₋₄alkyl,     -   (vi) —SH,     -   (vii) —S—C₁₋₄alkyl;     -   (viii) —NR⁷SO₂C₁₋₄alkyl, and     -   (ix) —NR⁷C(O)OR⁷,         R⁴ is selected from the group consisting of:     -   (a) —C₁₋₄alkyl,     -   (b) -haloC₁₋₄alkyl,     -   (c) —OH,     -   (d) —O—C₁₋₄alkyl,     -   (e) —O-haloC₁₋₄alkyl, and     -   (f) -halogen;         R⁵ is selected from the group consisting of:     -   (a) —C₃₋₁₂cycloalkyl,     -   (b) -aryl,     -   (c) -heteroaryl, and     -   (d) -heterocyclyl,         wherein each of choices (a) to (d) is optionally substituted         with 1 to 3 substituents independently selected from the group         consisting of:     -   (i) —C₁₋₄alkyl,     -   (ii) -halogen,     -   (iii) —NR⁷R⁸,     -   (iv) —OH,     -   (v) —O—C₁₋₄alkyl,     -   (vi) —SH, and     -   (vii) —S—C₁₋₄alkyl;         wherein each of the alkyl group of choices (i), (v) and (vii) is         optionally substituted with 1 to 5 substituents independently         selected from -halogen, -haloC₁₋₄alkyl, —OH, —O—C₁₋₄alkyl, —SH         and —S—C₁₋₄alkyl;         R⁶ is selected from the group consisting of:     -   (a) —C₁₋₆alkyl, and     -   (b) —C₀₋₆alkyl-aryl;         each R⁷ and each R⁸ are independently selected from the group         consisting of:     -   (a) —H,     -   (b) —C₁₋₆alkyl,     -   (c) —C₀₋₆alkyl-C₃₋₁₂cycloalkyl,     -   (d) —C₀₋₆alkyl-heterocyclyl,     -   (e) —C₀₋₆alkyl-heteroaryl,     -   (f) —C₀₋₆alkyl-aryl,     -   (g) —C₂₋₆alkenyl, and     -   (h) —C₂₋₆alkynyl,         wherein the alkyl group of choices (b)-(f), the alkenyl group of         choice (g), the cycloalkyl group of choice (c), and the alkynyl         group of (h) is optionally substituted with 1 to 3 groups         independently selected from:     -   (i) -halogen,     -   (ii) —C₁₋₄alkyl,     -   (iii) —C(O)C₁₋₄alkyl,     -   (iv) —OH,     -   (v) —OC₁₋₄alkyl,     -   (vi) —SH,     -   (vii) —SC₁₋₄alkyl,     -   (viii) —NH₂,     -   (ix) —NH(C₁₋₄alkyl), and     -   (x) —N(C₁₋₄alkyl)(C₁₋₄alkyl); or         R⁷, R⁸ and the nitrogen atom to which they are attached together         form a 3- to 7-membered monocyclic or 6- to 11-membered bicyclic         heterocycle optionally having an additional heteroatom selected         from O, S(O)_(p), and NR⁹, and wherein said heterocycle is         optionally substituted with 1 to 2 groups independently selected         from halogen;         R⁹ is selected from the group consisting of:     -   (a) —H,     -   (b) —C₁₋₄alkyl,     -   (c) —C(O)—C₁₋₄alkyl,     -   (d) —C(O)NH₂,     -   (e) —C(O)—NH(C₁₋₄alkyl),     -   (f) —C(O)—N(C₁₋₄alkyl)₂, and     -   (g) —C(O)O—C₁₋₄alkyl;         R¹⁰, R¹¹, and R¹² are independently selected from the group         consisting of: H, halogen, —OH and —C₁₋₆alkyl; or         R¹⁰, R¹¹ and the carbon atom to which they are attached together         form a C₃₋₁₂cycloalkyl or a heterocyclyl group;         k is 0, 1, 2, 3 or 4;         n and m are independently selected from 0, 1, 2 and 3, with the         proviso that n+m is 0, 1, 2, 3 or 4;         p is 0, 1 or 2.

In an eighteenth embodiment, for a compound of the seventeenth embodiment,

R² is —C₁₋₃alkyl-R⁵, and R⁵ is —C₃₋₁₂cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from the group consisting of:

-   -   (i) —C₁₋₄alkyl,     -   (ii) -halogen,     -   (iii) —O—C₁₋₄alkyl,     -   (iv) —S—C₁₋₄alkyl;         wherein each of the alkyl group of choices (i), (iii) and (iv)         is optionally substituted with 1 to 5 substituents independently         selected from -halogen, -haloC₁₋₄alkyl, —OH, —O—C₁₋₄alkyl, —SH         and —S—C₁₋₄alkyl.

In a nineteenth embodiment, for a compound having the formula (Ib) of any of the preceding embodiments,

W is —C(O)C(O)NH₂; X is —O— or —S(O)_(p)—; and Y is —C(O)—.

In a twentieth embodiment, for a compound of any of the preceding embodiments, R¹ is selected from the group consisting of:

-   -   (a) phenyl,     -   (b) naphthyl,     -   (c) 5- or 6-membered monocyclic heteroaryl ring, said ring         having a heteroatom selected from N, O and S, and optionally 1,         2 or 3 additional N atoms; and     -   (d) 8-, 9-, or 10-membered fused bicyclic heteroaryl ring, said         ring having a heteroatom selected from N, O and S, and         optionally 1, 2 or 3 additional N atoms;         wherein each of choices (a)-(d) is optionally substituted with 1         or 2 substituents independently selected from the group         consisting of:     -   (i) -halogen,     -   (ii) —CONR⁷R⁸,     -   (iii) —S(O)_(p)—C₁₋₆alkyl,     -   (iv) —S(O)_(p)—C₀₋₆alkyl-R⁵,     -   (v) —S(O)₂NR⁷R⁸,         wherein each of the alkyl group of choices (iii) and (iv) is         optionally substituted with 1 to 5 substituents independently         selected from -halogen, -haloC₁₋₄alkyl, —COR⁷, —CO₂R⁷, —CONR⁷R⁸,         —NR⁷R⁸, —OH, —O—C₁₋₄alkyl, —SH and —S—C₁₋₄alkyl.

In a twenty-first embodiment, for a compound of any of the preceding embodiments, n and m are each 1, and k is 0.

In a twenty-second embodiment, the compound of the first embodiment is a compound having the formula (Ic):

or a pharmaceutically acceptable salt, solvate, solvate of the salt or prodrug thereof, wherein

X is O or S(O)_(n);

R¹ is selected from the group consisting of:

-   -   (a) phenyl,     -   (b) naphthyl,     -   (c) 5- or 6-membered monocyclic heteroaryl ring, said ring         having a heteroatom selected from N, O and S, and optionally 1,         2 or 3 additional N atoms; and     -   (d) 8-, 9-, or 10-membered fused bicyclic heteroaryl ring, said         ring having a heteroatom selected from N, O and S, and         optionally 1, 2 or 3 additional N atoms;         wherein each of choices (a)-(d) is optionally substituted with 1         or 2 substituents independently selected from the group         consisting of:     -   (i) -halogen,     -   (ii) —CONR⁷R⁸,     -   (iii) —S(O)_(p)—C₁₋₆alkyl,     -   (iv) —S(O)_(p)—C₀₋₆alkyl-R⁵,     -   (v) —S(O)₂NR⁷R⁸,         wherein each of the alkyl group of choices (iii) and (iv) is         optionally substituted with 1 to 5 substituents independently         selected from -halogen, -haloC₁₋₄alkyl, —COR⁷, —CO₂R⁷, —CONR⁷R⁸,         —NR⁷R⁸, —OH, —O—C₁₋₄alkyl, —SH and —S—C₁₋₄alkyl.

In a twenty-third embodiment, for a compound of the twenty-second embodiment, R¹ is selected from naphthyl, imidazo[1,2-a]pyridinyl, quinolinyl, indazolyl, benzotriazolyl, benzisoxazolyl, benzoxazolyl, benzthiazolyl, benzofuranyl, indolyl, benzimidazolyl, and isoquinolinone.

In a twenty-fourth embodiment, for a compound of the twenty-second embodiment, R¹ is phenyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of:

-   -   (i) -halogen,     -   (ii) —CONR⁷R⁸,     -   (iii) —S(O)_(p)—C₁₋₆alkyl,     -   (iv) —S(O)_(p)—C₀₋₆alkyl-R⁵,     -   (v) —S(O)₂NR⁷R⁸,         wherein each of the alkyl group of choices (iii) and (iv) is         optionally substituted with 1 to 5 substituents independently         selected from -halogen, -haloC₁₋₄alkyl, —COR⁷, —CO₂R⁷, —CONR⁷R⁸,         —NR⁷R⁸, —OH, —O—C₁₋₄alkyl, —SH and —S—C₁₋₄alkyl.

In a twenty-fifth embodiment, the compound of the first embodiment is selected from the group consisting of:

-   tert-butyl     4-((2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamido)-4-(2-amino-2-oxoacetyl)piperidine-1-carboxylate; -   (2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; -   (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-(methylsulfonyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; -   (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-(piperidin-1-ylsulfonyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; -   N—((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)carbamoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidin-1-yl)-3-cyclohexyl-1-oxopropan-2-yl)imidazo[1,2-a]pyridine-6-carboxamide; -   (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-2-(4-cyanobenzamido)-3-cyclohexylpropanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; -   N—((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)carbamoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidin-1-yl)-3-cyclohexyl-1-oxopropan-2-yl)quinoline-3-carboxamide; -   N—((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)carbamoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidin-1-yl)-3-cyclohexyl-1-oxopropan-2-yl)-1H-indazole-7-carboxamide; -   (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-((2-methoxyethyl)sulfonyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; -   (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-((difluoromethyl)sulfonyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; -   (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-2-(4-((2-amino-2-oxoethyl)sulfonyl)benzamido)-3-cyclohexylpropanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; -   (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyclohexyl-2-(6-methoxy-2-naphthamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; -   (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyclohexyl-2-(1-methoxy-2-naphthamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; -   (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyclohexyl-2-(6-(difluoromethoxy)-2-naphthamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; -   (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyclohexyl-2-(6-(trifluoromethoxy)-2-naphthamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; -   (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; -   (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-(2-hydroxypropan-2-yl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; -   (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-(2,2,2-trifluoro-1,1-dihydroxyethyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; -   (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((2R)-3-cyclohexyl-2-(4-(2,2,2-trifluoro-1-hydroxyethyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; -   N—((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)carbamoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidin-1-yl)-3-cyclohexyl-1-oxopropan-2-yl)benzo[d]isoxazole-3-carboxamide; -   N—((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)carbamoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidin-1-yl)-3-cyclohexyl-1-oxopropan-2-yl)benzo[d]oxazole-2-carboxamide; -   N—((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)carbamoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidin-1-yl)-3-cyclohexyl-1-oxopropan-2-yl)benzo[d]thiazole-2-carboxamide; -   (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-2-(benzofuran-5-carboxamido)-3-cyclohexylpropanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; -   N—((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)carbamoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidin-1-yl)-3-cyclohexyl-1-oxopropan-2-yl)-1H-indole-6-carboxamide; -   N—((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)carbamoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidin-1-yl)-3-cyclohexyl-1-oxopropan-2-yl)-1H-indole-2-carboxamide; -   (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-fluorobenzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; -   (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-(3-hydroxyoxetan-3-yl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; -   (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-(isopropylsulfonyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; -   (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-(cyclopropylsulfonyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; -   N—((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)tetrahydro-2H1-pyran-4-yl)carbamoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidin-1-yl)-3-cyclohexyl-1-oxopropan-2-yl)-1H-indazole-6-carboxamide; -   N—((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)carbamoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidin-1-yl)-3-cyclohexyl-1-oxopropan-2-yl)-1H-benzo[d][1,2,3]triazole-6-carboxamide; -   N—((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)carbamoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidin-1-yl)-3-cyclohexyl-1-oxopropan-2-yl)-1H-benzo[d]imidazole-2-carboxamide; -   N—((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)carbamoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidin-1-yl)-3-cyclohexyl-1-oxopropan-2-yl)-1H-benzo[d]imidazole-6-carboxamide; -   (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyclohexyl-2-(3-fluoro-4-(methylsulfonyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; -   (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyclohexyl-2-(3-methyl-4-(methylsulfonyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; -   (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-(cyclopentylsulfonyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; -   (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-(ethylsulfonyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; -   (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-((trifluoromethyl)sulfonyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; -   (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-((2,2-difluoroethyl)sulfonyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; -   (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-(N,N-dimethylsulfamoyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; -   (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-sulfamoylbenzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; -   (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-(N-cyclopropylsulfamoyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; -   (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-(pyrrolidin-1-ylsulfonyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; -   (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-(N,N-diethylsulfamoyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; -   (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-(morpholinosulfonyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; -   (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyclohexyl-2-(3-((difluoromethyl)sulfonyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; -   (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyclohexyl-2-(2-((difluoromethyl)sulfonyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; -   (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-2-(4-(cyclobutylsulfonyl)benzamido)-3-cyclohexylpropanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; -   (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-2-(4-(N-cyclobutylsulfamoyl)benzamido)-3-cyclohexylpropanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; -   (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-(N-(2,2,2-trifluoroethyl)sulfamoyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; -   (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-(N-(prop-2-yn-1-yl)sulfamoyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; -   (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-(N-(cyclopropylmethyl)sulfamoyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; -   (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-(N-(2,2-difluoroethyl)sulfamoyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; -   (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyclohexyl-2-(6-(oxetan-3-yloxy)-2-naphthamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; -   (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyclohexyl-2-(6-(oxetan-3-yl)-2-naphthamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; -   (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-(N-(3,3-difluorocyclobutyl)sulfamoyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; -   (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyclohexyl-2-(3-phenylureido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; -   (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyclohexyl-2-(3-(naphthalen-2-yl)ureido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; -   (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyclohexyl-2-(3-(4-(trifluoromethyl)phenyl)ureido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; -   (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyclohexyl-2-(3-(1-methyl-1H-indol-4-yl)ureido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; -   (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-2-(3-(3-chloro-4-fluorophenyl)ureido)-3-cyclohexylpropanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; -   (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyclohexyl-2-(3-cyclohexylureido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; -   (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyclohexyl-2-(3-(naphthalen-1-yl)ureido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; -   (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyclohexyl-2-(3-(4-phenyltetrahydro-2H-pyran-4-yl)ureido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; -   (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-2-(3-benzylureido)-3-cyclohexylpropanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; -   (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-2-(3-(4-cyanophenyl)ureido)-3-cyclohexylpropanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; -   (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyclohexyl-2-(3-(4-(methylsulfonyl)phenyl)ureido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; -   (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyclohexyl-2-(naphthalene-2-sulfonamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; -   (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyclohexyl-2-(3,4-difluorophenylsulfonamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; -   (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-(difluoromethoxy)phenylsulfonamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; -   (2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-(3-(2-amino-2-oxoacetyl)tetrahydrofuran-3-yl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; -   (2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-(4-(2-amino-2-oxoacetyl)oxepan-4-yl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; -   (2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N—((R)-4-(2-amino-2-oxoacetyl)oxepan-4-yl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; -   (2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N—((S)-4-(2-amino-2-oxoacetyl)oxepan-4-yl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; -   (2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; -   (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-((difluoromethyl)sulfonyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; -   (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-(methylsulfonyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; -   N—((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)carbamoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidin-1-yl)-3-cyclohexyl-1-oxopropan-2-yl)picolinamide; -   (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-(ethylsulfonyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; -   N—((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)carbamoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidin-1-yl)-3-cyclohexyl-1-oxopropan-2-yl)imidazo[1,2-a]pyridine-6-carboxamide; -   N—((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)carbamoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidin-1-yl)-3-cyclohexyl-1-oxopropan-2-yl)-1-oxo-1,2-dihydroisoquinoline-3-carboxamide; -   (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-(cyclopropylsulfonyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; -   (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-(N-cyclopropylsulfamoyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; -   N—((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)carbamoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidin-1-yl)-3-cyclohexyl-1-oxopropan-2-yl)-2-methyl-2H-benzo[d][1,2,3]triazole-5-carboxamide; -   N—((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)carbamoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidin-1-yl)-3-cyclohexyl-1-oxopropan-2-yl)-1-methyl-1H-benzo[d][1,2,3]triazole-6-carboxamide; -   N—((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)carbamoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidin-1-yl)-3-cyclohexyl-1-oxopropan-2-yl)-1-methyl-1H-benzo[d][1,2,3]triazole-5-carboxamide; -   (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-((2-methoxyethyl)sulfonyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; -   N—((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)carbamoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidin-1-yl)-3-cyclohexyl-1-oxopropan-2-yl)-1H-benzo[d][1,2,3]triazole-5-carboxamide; -   N¹—((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)carbamoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidin-1-yl)-3-cyclohexyl-1-oxopropan-2-yl)terephthalamide; -   (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)-1-((R)-2-benzamido-3-cyclohexylpropanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; -   N—((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)carbamoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidin-1-yl)-3-cyclohexyl-1-oxopropan-2-yl)isonicotinamide; -   (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-(N-(prop-2-yn-1-yl)sulfamoyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; -   (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-(N-(3,3-difluorocyclobutyl)sulfamoyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; -   (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-(N-(oxetan-3-yl)sulfamoyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; -   (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-(morpholinosulfonyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; -   (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-(N-methylsulfamoyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; -   (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-(N,N-dimethylsulfamoyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; -   (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-(N-ethylsulfamoyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; -   (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-(isopropylsulfonyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; -   (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-((cyclopropylmethyl)sulfonyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; -   (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-(N-(2,2-difluoroethyl)sulfamoyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; -   (2S,4S)-1-((R)-2-(4-((4-acetylpiperazin-1-yl)sulfonyl)benzamido)-3-cyclohexylpropanoyl)-N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; -   (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-(pyrrolidine-1-carbonyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; -   (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)-1-((R)-2-(4-(cyclobutylsulfonyl)benzamido)-3-cyclohexylpropanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; -   N¹—((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)carbamoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidin-1-yl)-3-cyclohexyl-1-oxopropan-2-yl)-N⁴,N⁴-dimethylterephthalamide; -   (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-(N-(1-methylcyclopropyl)sulfamoyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; -   (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-((4-methylpiperazin-1-yl)sulfonyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; -   (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)-1-((R)-2-(4-(azetidin-1-ylsulfonyl)benzamido)-3-cyclohexylpropanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; -   (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-(pyrrolidin-1-ylsulfonyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; -   (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-(N-(cyclopropylmethyl)sulfamoyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; -   (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)-1-((R)-2-(4-(N-cyclobutylsulfamoyl)benzamido)-3-cyclohexylpropanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; -   (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-(N-(2,2,2-trifluoroethyl)sulfamoyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; -   (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-(N-(tetrahydro-2H-thiopyran-4-yl)sulfamoyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; -   (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-((3,3-difluoroazetidin-1-yl)sulfonyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; -   (2S,4S)-1-((R)-2-(4-(2-oxa-6-azaspiro[3.3]heptan-6-ylsulfonyl)benzamido)-3-cyclohexylpropanoyl)-N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; -   (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-(N-(3,3-dimethyl-2-oxobutyl)sulfamoyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; -   (2S,4S)—N-(4-(2-amino-2-oxoacetyl)-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-(pyrrolidin-1-ylsulfonyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; -   (2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-(4-(2-amino-2-oxoacetyl)-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; -   (2S,4S)—N-(4-(2-amino-2-oxoacetyl)-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-(methylsulfonyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; -   (2S,4S)—N-(4-(2-amino-2-oxoacetyl)-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-((difluoromethyl)sulfonyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; -   N—((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)carbamoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidin-1-yl)-3-cyclohexyl-1-oxopropan-2-yl)quinoline-3-carboxamide; -   N—((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)carbamoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidin-1-yl)-3-cyclohexyl-1-oxopropan-2-yl)-1H-indazole-7-carboxamide; -   (2S,4S)—N-(4-(2-amino-2-oxoacetyl)-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1-((R)-2-(4-cyanobenzamido)-3-cyclohexylpropanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; -   N—((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)carbamoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidin-1-yl)-3-cyclohexyl-1-oxopropan-2-yl)-1H-indazole-6-carboxamide; -   N¹—((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)carbamoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidin-1-yl)-3-cyclohexyl-1-oxopropan-2-yl)terephthalamide; -   (2S,4S)—N-(4-(2-amino-2-oxoacetyl)-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-nitrobenzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; -   (2S,4S)—N-(4-(2-amino-2-oxoacetyl)-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1-((R)-2-(4-bromobenzamido)-3-cyclohexylpropanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; -   (2S,4S)—N-(4-(2-amino-2-oxoacetyl)-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1-((R)-2-(4-chloro-2,5-difluorobenzamido)-3-cyclohexylpropanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; -   (2S,4S)—N-(4-(2-amino-2-oxoacetyl)-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1-((R)-3-cyclohexyl-2-(3,4-dichlorobenzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; -   N—((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)carbamoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidin-1-yl)-3-cyclohexyl-1-oxopropan-2-yl)-6-hydroxynicotinamide; -   N—((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)carbamoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidin-1-yl)-3-cyclohexyl-1-oxopropan-2-yl)-1-hydroxyisoquinoline-3-carboxamide; -   N—((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)carbamoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidin-1-yl)-3-cyclohexyl-1-oxopropan-2-yl)-7-fluoroquinoline-3-carboxamide; -   N—((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)carbamoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidin-1-yl)-3-cyclohexyl-1-oxopropan-2-yl)-7-chloroquinoline-3-carboxamide; -   (2S,4S)—N-(4-(2-amino-2-oxoacetyl)-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-(N-cyclopropylsulfamoyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; -   (2S,4S)—N-(4-(2-amino-2-oxoacetyl)-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1-((R)-2-(4-(N-cyclobutylsulfamoyl)benzamido)-3-cyclohexylpropanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; -   (2S,4S)—N-(4-(2-amino-2-oxoacetyl)-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-(N-(spiro[3.3]heptan-2-yl)sulfamoyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; -   (2S,4S)—N-(4-(2-amino-2-oxoacetyl)-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-(N-(2,2-difluoroethyl)sulfamoyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; -   (2S,4S)—N-(4-(2-amino-2-oxoacetyl)-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-(piperidin-1-ylsulfonyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; -   (2S,4S)—N-(4-(2-amino-2-oxoacetyl)-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1-((R)-2-(4-(N-(tert-butyl)sulfamoyl)benzamido)-3-cyclohexylpropanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; -   (2S,4S)—N-(4-(2-amino-2-oxoacetyl)-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-(N-phenylsulfamoyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; -   (2S,4S)—N-(4-(2-amino-2-oxoacetyl)-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-(N-cyclopropyl-N-methylsulfamoyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; -   (2S,4S)—N-(4-(2-amino-2-oxoacetyl)-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-(N-cyclopropyl-N-ethylsulfamoyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; -   (2S,4R)—N-(4-(2-amino-2-oxoacetyl)-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-(N-cyclopentylsulfamoyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; -   (2S,4S)—N-(4-(2-amino-2-oxoacetyl)-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-(N,N-dicyclopropylsulfamoyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; -   (2S,4S)—N-(4-(2-amino-2-oxoacetyl)-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1-((R)-3-cyclohexyl-2-(naphthalene-2-sulfonamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; -   (2S,4S)—N-(4-(2-amino-2-oxoacetyl)-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1-((R)-3-cyclohexyl-2-(3-(naphthalen-2-yl)ureido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; -   (2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-(4-(2-amino-2-oxoacetyl)-1-oxidotetrahydro-2H-thiopyran-4-yl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; -   (2S,4S)—N-(4-(2-amino-2-oxoacetyl)-1-oxidotetrahydro-2H-thiopyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-((difluoromethyl)sulfonyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; -   (2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-(3-(2-amino-2-oxoacetyl)tetrahydrothiophen-3-yl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; -   (2S,4R)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-(3-(2-amino-2-oxoacetyl)-1-oxidotetrahydrothiophen-3-yl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; -   (2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-(3-(2-amino-2-oxoacetyl)-1,1-dioxidotetrahydrothiophen-3-yl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; -   (2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-(3-(2-amino-2-oxoacetyl)-1,1-dioxidotetrahydro-2H-thiopyran-3-yl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; -   (2S,4S)—N—((R)-4-((2-amino-2-oxoacetyl)oxepan-4-yl)-1-((R)-3-cyclohexyl-2-(4-((difluoromethyl)sulfonyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; -   (2S,4S)—N—((S)-4-((2-amino-2-oxoacetyl)oxepan-4-yl)-1-((R)-3-cyclohexyl-2-(4-((difluoromethyl)sulfonyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; -   (2S,4S)—N—((R)-4-(2-amino-2-oxoacetyl)oxepan-4-yl)-1-((R)-3-cyclohexyl-2-(4-(cyclopropylsulfonyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; -   (2S,4S)—N—((S)-4-(2-amino-2-oxoacetyl)oxepan-4-yl)-1-((R)-3-cyclohexyl-2-(4-(cyclopropylsulfonyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; -   (2S,4S)—N—((R)-4-(2-amino-2-oxoacetyl)oxepan-4-yl)-1-((R)-3-cyclohexyl-2-(4-(N-cyclopropylsulfamoyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; -   (2S,4S)—N—((S)-4-(2-amino-2-oxoacetyl)oxepan-4-yl)-1-((R)-3-cyclohexyl-2-(4-(N-cyclopropylsulfamoyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; -   (2S,4R)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-4-hydroxypyrrolidine-2-carboxamide; -   (S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-4-oxopyrrolidine-2-carboxamide; -   (2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-4-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)pyrrolidine-2-carboxamide; -   (2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-4-(6-oxopyridazin-1(6H)-yl)pyrrolidine-2-carboxamide; -   (2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-4-(3-oxo-[1,2,4]triazolo[4,3-a]pyridin-2(3H)-yl)pyrrolidine-2-carboxamide; -   (2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-4-(1,3-dioxoisoindolin-2-yl)pyrrolidine-2-carboxamide; -   (2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-4-((5-methylisoxazol-3-yl)oxy)pyrrolidine-2-carboxamide; -   (2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-4-(3-chloro-6-oxopyridazin-1(6H)-yl)pyrrolidine-2-carboxamide; -   (2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-4-(2-oxopyridin-1(2H)-yl)pyrrolidine-2-carboxamide;     and -   (4-((2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamido)tetrahydro-2H-pyran-4-yl)boronic     acid;     or a pharmaceutically acceptable salt, solvate, salt of the solvate,     or prodrug thereof.

In a twenty-sixth embodiment, the present disclosure provides a pharmaceutical composition comprising a compound of any of the first through the twenty-fifth embodiments, and a pharmaceutically acceptable carrier.

In a twenty-seventh embodiment, the present disclosure provides a method of preventing, or treating a disease of the eye selected from dry-AMD, wet-AMD, geographic atrophy, diabetic retinopathy, retinopathy of prematurity, polypoidal choroidal vasculopathy, and degeneration of retinal or photoreceptor cells, comprising: administering to a subject in need thereof a therapeutically effective amount of a compound according to any of the first through twenty-fifth embodiments, or a pharmaceutically acceptable salt, solvate, solvate of the salt or prodrug thereof, or the pharmaceutical composition of the twenty-sixth embodiment.

In a twenty-eighth embodiment, for the method of the twenty-seventh embodiment, the method of prevention is selected from delaying the onset of disease and reducing the risk of developing a disease of the eye, wherein the disease of the eye is selected from dry-AMD, wet-AMD, geographic atrophy, diabetic retinopathy, retinopathy of prematurity, polypoidal choroidal vasculopathy, and degeneration of retinal or photoreceptor cells.

In a twenty-ninth embodiment, for the method of the twenty-seventh embodiment the method of treating a disease of the eye is selected from controlling, alleviating, and slowing the progression of, wherein the disease is selected from dry-AMD, wet-AMD, geographic atrophy, diabetic retinopathy, retinopathy of prematurity, polypoidal choroidal vasculopathy, and degeneration of retinal or photoreceptor cells.

In a thirtieth embodiment, for the method of any one of the twenty-seventh through the twenty-ninth embodiments, the disease is geographic atrophy.

In a thirty-first embodiment, the present disclosure provides a method of inhibiting HtrAl protease activity in an eye, comprising administering to a subject in need thereof a therapeutically effective amount of any one of the compounds of the first through twenty-fifth embodiments or a pharmaceutically acceptable salt, solvate, solvate of the salt or prodrug thereof, or the pharmaceutical composition of the twenty-sixth embodiment.

Any of the features of an embodiment is applicable to all embodiments identified herein. Moreover, any of the features of an embodiment is independently combinable, partly or wholly with other embodiments described herein in any way, e.g., one, two, or three or more embodiments may be combinable in whole or in part. Further, any of the features of an embodiment may be made optional to other embodiments. Any embodiment of a method can comprise another embodiment of a compound, and any embodiment of a compound can be configured to perform a method of another embodiment.

Definitions

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art. All patents, applications, published applications and other publications referenced herein are incorporated by reference in their entirety unless stated otherwise. In the event that there are a plurality of definitions for a term herein, those in this section prevail unless stated otherwise.

The term “patient” includes mammals such as mice, rats, cows, sheep, pigs, rabbits, goats, horses, monkeys, dogs, cats, and humans.

The term “halo” or “halogen” refers to any radical of fluorine, chlorine, bromine or iodine.

The term “alkyl” refers to a saturated hydrocarbon chain that may be a straight chain or branched chain, containing the indicated number of carbon atoms. For example, C₁₋₆alkyl indicates that the group may have from 1 to 6 (inclusive) carbon atoms in it. In some embodiments, an alkyl is a C₁₋₆alkyl which represents a straight-chain or branched saturated hydrocarbon radical having 1 to 6 carbon atoms. Examples of alkyl include without limitation methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. The notation “C_(0-n)alkyl” indicates the absence of an alkyl moiety, or the presence of an alkyl moiety having 1 to n carbon atoms. Thus, for example, the term “C₀₋₆alkyl-R⁵” indicates that the R⁵ group is attached directly to the parent moiety, or that there is an intervening alkyl group of 1 to 6 carbon atoms between R⁵ and the parent moiety; such an intervening group may be, for example, —CH₂—, —CH₂CH₂—, —CH(CH₃)— and —C(CH₃)₂—.

The term “haloalkyl” refers to an alkyl group in which at least one hydrogen atom is replaced by halo. In some embodiments, more than one hydrogen atom (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14) are replaced by halo. In these embodiments, the hydrogen atoms can each be replaced by the same halogen (e.g., fluoro) or the hydrogen atoms can be replaced by a combination of different halogens (e.g., fluoro and chloro). “Haloalkyl” also includes alkyl moieties in which all hydrogens have been replaced by halo (sometimes referred to herein as perhaloalkyl, e.g., perfluoroalkyl, such as trifluoromethyl).

As referred to herein, the term “alkoxy” refers to a group of formula —O-(alkyl). Alkoxy can be, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, iso-butoxy, sec-butoxy, pentoxy, 2-pentoxy, 3-pentoxy, or hexyloxy. Likewise, the term “thioalkoxy” refers to a group of formula —S-(alkyl). The terms “haloalkoxy” and “thiohaloalkoxy” refer to —O-(haloalkyl) and —S-(haloalkyl), respectively. The term “sulfhydryl” refers to —SH.

The term “aralkyl” refers to an alkyl moiety in which an alkyl hydrogen atom is replaced by an aryl group. One of the carbons of the alkyl moiety serves as the point of attachment of the aralkyl group to another moiety. Non-limiting examples of “aralkyl” include benzyl, 2-phenylethyl, and 3-phenylpropyl groups.

The term “alkenyl” refers to a straight or branched hydrocarbon chain containing the indicated number of carbon atoms and having one or more carbon-carbon double bonds. Alkenyl groups can include, e.g., vinyl, allyl, 1-butenyl, and 2-hexenyl. In some embodiments, an alkenyl is a C₂₋₆alkenyl.

The term “alkynyl” refers to a straight or branched hydrocarbon chain containing the indicated number of carbon atoms and having one or more carbon-carbon triple bonds. Alkynyl groups can include, e.g., ethynyl, propargyl, 1-butynyl, and 2-hexynyl. In some embodiments, an alkynyl is a C₂₋₆alkynyl.

The term “heterocycle”, “heterocyclyl” or “heterocyclic” as used herein except where noted, represents a stable 4-, 5-, 6- or 7-membered monocyclic- or a stable 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered bicyclic heterocyclic ring system which comprises at least one non-aromatic (i.e. saturated or partially unsaturated) ring which consists of carbon atoms and from one to four, preferably up to three, heteroatoms selected from the group consisting of N, O and S, wherein the nitrogen and sulfur atoms may optionally be oxidized as N-oxide, sulfoxide or sulfone, and wherein the nitrogen atom may optionally be quaternized. A heterocycle can be bonded via a ring carbon atom or, if available, via a ring nitrogen atom. Bicyclic heterocyclic ring systems may be fused, bridged, or spiro bicyclic heterocyclic ring system(s). In some embodiments, heterocyclyl is monocyclic having 4 to 7, preferably 4 to 6, ring atoms, of which 1 or 2 are heteroatoms independently selected from the group consisting of N, O and S. In some embodiments, a heterocyclyl group is bicyclic, and in which case, the second ring may be an aromatic or a non-aromatic ring which consists of carbon atoms and from one to four, preferably up to three, heteroatoms independently selected from the group consisting of N, O and S, or the second ring may be a benzene ring, or a “cycloalkyl”, or a “cycloalkenyl”, as defined herein. Examples of such heterocyclic groups include, but are not limited to azetidine, chroman, dihydrofuran, dihydropyran, dioxane, dioxolane, hexahydroazepine, imidazolidine, imidazoline, indoline, isochroman, isoindoline, isothiazoline, isothiazolidine, isoxazoline, isoxazolidine, morpholine, oxazoline, oxazolidine, oxetane, piperazine, piperidine, dihydropyridine, tetrahydropyridine, dihydropyridazine, pyran, pyrazolidine, pyrazoline, pyrrolidine, pyrroline, tetrahydrofuran, tetrahydropyran, thiamorpholine, tetrahydrothiophene, thiazoline, thiazolidine, thiomorpholine, thietane, thiolane, sulfolane, 1,3-dioxolane, 1,3-oxazolidine, 1,3-thiazolidine, tetrahydrothiopyran, tetrahydrotriazine, 1,3-dioxane, 1,4-dioxane, hexahydrotriazine, tetrahydro-oxazine, tetrahydropyrimidine, perhydroazepine, perhydro-1,4-diazepine, perhydro-1,4-oxazepine, 7-azabicyclo[2.2.1]heptane, 3-azabicyclo[3.2.0]heptane, 7-azabicyclo[4.1.0]heptane, 2,5-diazabicyclo[2.2.1]heptane, 2-oxa-5-azabicyclo[2.2.1]heptane, tropane, 2-oxa-6-azaspiro[3.3]heptane, dihydrobenzofuran, dihydrobenzimidazolyl, dihydrobenzoxazole, and dihydrobenzothiazolyl, and N-oxides or sulfones or sulfoxides thereof.

The term “cycloalkyl” refers to a fully saturated monocyclic, bicyclic, tricyclic or other polycyclic hydrocarbon group having the indicated number of ring carbon atoms. Multicyclic cycloalkyl may be fused, bridged or spiro ring systems. Cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl (bicyclo[2.2.1]heptyl), decalinyl, adamantyl, spiropentyl, bicyclo[2.1.0]pentyl, bicyclo[3.1.0]hexyl, spiro[2.4]heptyl, spiro[2.5]octyl, bicyclo[5.1.0]octyl, spiro[2.6]nonyl, bicyclo[2.2.0]hexyl, spiro[3.3]heptyl, bicyclo[4.2.0]octyl, bicyclo[2.2.2]octyl, and spiro[3.5]nonyl. In some embodiments, cycloalkyl is a monocyclic C₃₋₈cycloalkyl. In other embodiments, cycloalkyl is a bi- or tricyclic C₅₋₁₂cycloalkyl. In other embodiments, cycloalkyl is a spirocyclic C₅₋₁₂cycloalkyl.

The term “cycloalkenyl” refers to partially unsaturated monocyclic, bicyclic, tricyclic, or other polycyclic hydrocarbon groups. A ring carbon (e.g., saturated or unsaturated) is the point of attachment of the cycloalkenyl substituent. Cycloalkenyl moieties can include, e.g., cyclopentenyl, cyclohexenyl, cyclohexadienyl, or norbornenyl. In some embodiments, a cycloalkenyl is a C₄₋₁₀cycloalkenyl. In other embodiments, a cycloalkenyl is a C₄₋₆cycloalkenyl. In some embodiments, a cycloalkenyl is monocyclic. In some embodiments, a cycloalkenyl is bicyclic.

The term “aryl” as used herein, is intended to mean any stable monocyclic or bicyclic carbon ring of up to 6 members in each ring, wherein at least one ring is aromatic. Examples of aryl include phenyl, naphthyl, tetrahydronaphthyl, indanyl, or biphenyl.

The term “heteroaryl”, as used herein except where noted, represents a stable 5-, 6- or 7-membered monocyclic- or stable 9 or 10-membered fused bicyclic ring system which comprises at least one aromatic ring, which consists of carbon atoms and from one to four, preferably up to three, heteroatoms selected from the group consisting of N, O and S wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. In the case of a “heteroaryl” which is a bicyclic group, the second ring need not be aromatic and need not comprise a heteroatom. Accordingly, bicyclic “heteroaryl” includes, for example, a stable 5- or 6-membered monocyclic aromatic ring consisting of carbon atoms and from one to four, preferably up to three, heteroatoms, as defined immediately above, fused to a benzene ring, or a second monocyclic “heteroaryl”, or a “heterocyclyl”, a “cycloalkyl”, or a “cycloalkenyl”, as defined above. Examples of heteroaryl groups include, but are not limited to, benzimidazole, benzopyrazole, benzisothiazole, benzisoxazole, benzofuran, isobenzofuran, benzothiazole, benzothiophene, benzotriazole, benzoxazole, cinnoline, furan, furazan, imidazole, indazole, indole, indolizine, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, phthalazine, pteridine, purine, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, quinazoline, quinoline, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, triazine, triazole, benzimidazole, benzothiadiazole, isoindole, pyrrolopyridines, imidazopyridines such as imidazo[1,2-a]pyridine, pyrazolopyridine, pyrrolopyrimidine and N-oxides thereof.

The term “acyl”, as used herein, refers to those groups derived from an organic acid by removal of the hydroxy portion of the acid. Accordingly, acyl is meant to include, for example, acetyl, propionyl, butyryl, decanoyl, pivaloyl, benzoyl and the like.

As used herein, the term “fused” refers to a connectivity between two rings in which two adjacent atoms sharing at least one bond (saturated or unsaturated) are common to the rings. For example, in the following structure, rings A and B are fused

Examples of fused ring structures include, but are not limited to, decahydronaphthalene, 1H-indole, quinolone, chromane, bicyclo[2.1.0]pentane and 6,7,8,9-tetrahydro-5H-benzo[7]annulene.

As used herein, the term “bridged” refers to a connectivity wherein three or more atoms are shared between two rings. The following structures

are examples of “bridged” rings because the indicated atoms are shared between at least two rings. Examples of bridged ring structures include, but are not limited to, bicyclo[1.1.1]pentane, 2-oxabicyclo[1.1.1]pentane, 5-azabicyclo[2.1.1]hexane, 6-azabicyclo[3.1.1]heptane, adamantane and norbornane.

As used herein, the term “spiro” refers to a connectivity between two rings wherein the rings have only one atom in common. For example, in the structure

rings C and D are joined by a spiro connection. Examples of spiro connected ring structures include, but are not limited to, spiro[3.3]heptane, 2,6-diazaspiro[3.3]heptane, 2-oxa-6-azaspiro[3.3]heptane, spiro[4.5]decane and 2,6-dioxaspiro[3.3]heptane.

For each of the organic radicals defined above, any atom can be optionally substituted, e.g., by one or more substituents.

Unless otherwise specified, when a bond is depicted in a chemical structure with

, it is meant that the bond is located at a stereocenter in which the structure may have either the S or R configuration as understood under the Cahn-Ingold System for naming enantiomers. For example, the

notation can indicate that the bond at the given position can be either a

or a

. The presence of the

does not limit the exemplified compound to only a racemate, but can include all possible stereoconfigurations.

It is understood that in structural formulae containing the Y variable in which Y may be —NHC(O)—, the group is meant to be unidirectional, i.e. the carbonyl is linked to the nitrogen to form a urea group.

The term “treating”, “treat”, or “treatment” refers generally to controlling, alleviating, ameliorating, slowing the progress of or eliminating a named condition once the condition has been established. In addition to its customary meaning, the term “preventing”, “prevent”, or “prevention” also refers to delaying the onset of, or reducing the risk of developing a named condition or of a process that can lead to the condition, or the recurrence of symptoms of a condition.

The term “therapeutically effective amount” or “effective amount” is an amount sufficient to effect beneficial or desired clinical results. An effective amount can be administered in one or more administrations. An effective amount is typically sufficient to palliate, ameliorate, stabilize, reverse, slow or delay the progression of the disease state.

Compound Forms and Salts

The compounds of this disclosure may contain one or more asymmetric centers and thus occur as racemates and racemic mixtures, enantiomerically enriched mixtures, single enantiomers, individual diastereomers and diastereomeric mixtures. The compounds of the present disclosure may, either by nature of asymmetric centers or by restricted rotation, be present in the form of isomers (e.g., enantiomers, diastereomers).

It will also be appreciated that when two or more asymmetric centers are present in the compounds of the disclosure, several diastereomers and enantiomers of the exemplified structures will often be possible, and that pure diastereomers and pure enantiomers represent preferred embodiments. It is intended that pure stereoisomers, pure diastereomers, pure enantiomers, and mixtures thereof, are within the scope of the disclosure.

All isomers, whether separated, pure, partially pure, or in racemic mixture, of the compounds of this disclosure are encompassed within the scope of this disclosure. The purification of said isomers and the separation of said isomeric mixtures may be accomplished by standard techniques known in the art. For example, diastereomeric mixtures can be separated into the individual isomers by chromatographic processes or crystallization, and racemates can be separated into the respective enantiomers either by chromatographic processes on chiral phases or by resolution.

The compounds of the present disclosure include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as mixtures thereof. The compounds of the present disclosure may also be represented in multiple tautomeric forms, in such instances, the present disclosure expressly includes all tautomeric forms of the compounds described herein, even though only a single tautomeric form may be represented. In addition, where a term used in the present disclosure encompasses a group that may tautomerize, all tautomeric forms are expressly included thereunder. For example, hydroxy substituted heteroaryl includes 2-hydroxypyridine as well as 2-pyridone, 1-hydroxyisoquinoline as well as 1-oxo-1,2-dihydroisoquinoline, and the like. All such isomeric forms of such compounds are expressly included in the present disclosure.

The compounds of the present disclosure include the compounds themselves, as well as their salts, solvate, solvate of the salt and their prodrugs, if applicable. Salts for the purposes of the present disclosure are preferably pharmaceutically acceptable salts of the compounds according to the present disclosure. Salts which are not themselves suitable for pharmaceutical uses but can be used, for example, for isolation or purification of the compounds according to the disclosure are also included. A salt, for example, can be formed between an anion and a positively charged substituent (e.g., amino) on a compound described herein. Suitable anions include chloride, bromide, iodide, sulfate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, and acetate. Likewise, a salt can also be formed between a cation and a negatively charged substituent (e.g., carboxylate) on a compound described herein. Suitable cations include sodium ion, potassium ion, magnesium ion, calcium ion, and an ammonium cation such as tetramethylammonium ion.

As used herein, “pharmaceutically acceptable salts” refer to derivatives wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. When the compound of the present disclosure is basic, pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfonic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, benzenesulfonic, toluenesulfonic, naphthalenedisulfonic, methanesulfonic, ethanesulfonic, ethanedisulfonic, camphorsulfonic, gluconic, mandelic, mucic, pantothenic, oxalic, isethionic, and the like.

When the compound of the present disclosure is acidic, salts may be prepared from pharmaceutically acceptable non-toxic bases, including inorganic and organic bases. Such salts that may be prepared include lithium salt, sodium salt, potassium salt, magnesium salt, calcium salt, dicyclohexylamine salt, N-methyl-D-glucamine salt, tris(hydroxymethyl)methylamine salt, arginine salt, lysine salt, and the like.

Lists of suitable salts may be found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418; S. M. Berge et al., “Pharmaceutical Salts”, J. Pharm. Sci. 1977, 66, 1-19; and “Pharmaceutical Salts: Properties, Selection, and Use. A Handbook”; Wermuth, C. G. and Stahl, P. H. (eds.) Verlag Helvetica Chimica Acta, Zurich, 2002 [ISBN 3-906390-26-8]; each of which is incorporated herein by reference in its entirety.

Solvates in the context of the present disclosure are designated as those forms of the compounds according to the present disclosure which form a complex in the solid or liquid state by stoichiometric coordination with solvent molecules. Hydrates are a specific form of solvates, in which the coordination takes place with water. Hydrates are preferred solvates in the context of the present disclosure. The formation of solvates is described in greater detail in “Solvents and Solvent Effects in Organic Chemistry”; Reichardt, C. and Welton T.; John Wiley & Sons, 2011 [ISBN: 978-3-527-32473-6], the contents of which is incorporated herein by reference in its entirety. A person of ordinary skill in the art would recognize the solvates of the present disclosure.

The present disclosure also encompasses all suitable isotopic variants of the compounds according to the present disclosure, whether radioactive or not. An isotopic variant of a compound according to the present disclosure is understood to mean a compound in which at least one atom within the compound according to the present disclosure has been exchanged for another atom of the same atomic number, but with a different atomic mass than the atomic mass which usually or predominantly occurs in nature. Examples of isotopes which can be incorporated into a compound according to the present disclosure are those of hydrogen, carbon, nitrogen, oxygen, fluorine, chlorine, bromine and iodine, such as ²H (deuterium), ³H (tritium), ¹³C, ¹⁴C, ¹⁵N, ¹⁷O, ¹⁸O, ¹⁸F, ³⁶Cl, ⁸²Br, ¹²³I, ¹²⁴I, ¹²⁵I, ¹²⁹I and ¹³¹I. Particular isotopic variants of a compound according to the present disclosure, especially those in which one or more radioactive isotopes have been incorporated, may be beneficial, for example, for the examination of the mechanism of action or of the active compound distribution in the body. Due to comparatively easy preparability and detectability, especially compounds labelled with ³H, ¹⁴C and/or ¹⁸F isotopes are suitable for this purpose. In addition, the incorporation of isotopes, for example of deuterium, can lead to particular therapeutic benefits as a consequence of greater metabolic stability of the compound, for example an extension of the half-life in the body or a reduction in the active dose required. Such modifications of the compounds according to the present disclosure may therefore in some cases also constitute a preferred embodiment of the present disclosure. In some embodiments, hydrogen atoms of the compounds described herein may be replaced with deuterium atoms. Isotopic variants of the compounds according to the present disclosure can be prepared by processes known to those skilled in the art, for example by the methods described below and the methods described in the working examples, by using corresponding isotopic modifications of the particular reagents and/or starting compounds therein.

The present disclosure includes within its scope prodrugs of the compounds of Formula I. Prodrugs are generally drug precursors that, following administration to a subject are converted to an active, or a more active species via some process, such as conversion by chemical hydrolysis or a metabolic pathway. Thus, in the methods of treatment of the present disclosure, the terms “administration of” or “administering a” compound shall encompass the treatment of the various conditions described with the compound specifically disclosed or with a compound which may not be specifically disclosed, but which converts to the specified compound in vivo after administration to the patient. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in “Design of Prodrugs,” ed. H. Bundgaard, Elsevier, 1985 (Amsterdam, NL). Examples of prodrugs include C₁₋₆ alkyl esters of carboxylic acid groups and esters of boronic acids, which, upon administration to a subject, are capable of providing active compounds.

Esters of boronic acids are illustrated by Formula II:

wherein:

Y₁ and Y₂ are each independently selected from hydrogen, optionally substituted C₁₋₆alkyl, C₃₋₁₀cycloalkyl, C₁₋₆heterocycle, aryl and heteroaryl, or Y₁ and Y₂ are joined together to form the group

which represents an optionally substituted C₂₋₆alkyl in which a carbon atom may be replaced by O, S or N—CH₃, optionally substituted C₅₋₁₂cycloalkyl, optionally substituted heterocycle, optionally substituted aryl or optionally substituted heteroaryl. The optional substituents include, for example, hydroxyl, halogen and C₁₋₃alkoxy. As will be appreciated by one of skill in the art, the squiggly lines describe the point at which the moiety shown is attached to the parent molecule. Illustrating the boronic acid esters are:

Y₁ and Y₂ can also represent —B—O—B— to form a 6-membered trioxatriborinane or —B— to form a 4-membered dioxadiboretane.

In some embodiments, where W of Formula I is —C(O)C(O)NR⁷R⁸ (ketoamides), compounds of Formula I may be prepared as prodrugs. Examples of ketone prodrugs include but are not limited to ketimine, oxime, aminal, ketal, hemiaminal, hemiketal, thioketal, hydrated ketone which, upon administration to a subject, are capable of providing active compounds. Carbonyl derivatives of ketoamides are illustrated by Formula IIIa and IIIb:

wherein:

X₁ and X₂ are each independently selected from O, N and S;

Y₁ and Y₂ are each independently selected from hydrogen, optionally substituted C₁₋₆alkyl, C₃₋₁₀cycloalkyl, C₁₋₆heterocycle, or Y₁ and Y₂ are joined together to form the group:

wherein Y₁ and Y₂ forms an optionally substituted C₂₋₆alkyl, or an optionally substituted heterocycle. The optional substituents include, for example, hydroxyl, halogen and C₁₋₃alkoxy;

Y₃ is H, C₁₋₄alkyl, OH or O—C₁₋₄alkyl.

Illustrating the ketone prodrugs are:

Pharmaceutical Compositions

The term “pharmaceutical composition” as used herein is intended to encompass a product comprising the active ingredient(s), and the inert ingredient(s) that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the pharmaceutical compositions of the present disclosure encompass any composition made by admixing a compound of the present disclosure, or a pharmaceutically acceptable salt, or solvate or solvate of the salt thereof, and a pharmaceutically acceptable carrier.

The term “pharmaceutically acceptable carrier” refers to a carrier or an adjuvant that may be administered to a patient, together with a compound of the present disclosure, or a pharmaceutically acceptable salt, solvate, salt of the solvate or prodrug thereof, and which does not destroy the pharmacological activity thereof and is nontoxic when administered in doses sufficient to deliver a therapeutic amount of the compound.

The amount administered depends on the compound formulation, route of administration, etc. and is generally empirically determined in routine trials, and variations will necessarily occur depending on the target, the host, and the route of administration, etc. Generally, the quantity of active compound in a unit dose of preparation may be varied or adjusted from about 1, 3, 10 or 30 to about 30, 100, 300 or 1000 mg, according to the particular application. For convenience, the total daily dosage may be divided and administered in portions during the day if desired.

Pharmaceutical compositions of the present disclosure for injection comprise pharmaceutically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

These pharmaceutical compositions may also contain adjuvants such as preservative, wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of micro-organisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents such as sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents that delay absorption such as aluminium monostearate and gelatin. If desired, and for more effective distribution, the compounds can be incorporated into slow release or targeted delivery systems such as polymer matrices, liposomes, and microspheres.

The pharmaceutical compositions that are injectable formulations can be sterilised, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilising agents in the form of sterile solid pharmaceutical compositions that can be dissolved or dispersed in sterile water or other sterile injectable medium just prior to use.

Solid dosage forms of the instant pharmaceutical compositions for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

Solid pharmaceutical compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

The solid dosage forms of the instant pharmaceutical compositions of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a formulation that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding pharmaceutical compositions which can be used include polymeric substances and waxes.

The active compounds can also be in microencapsulated form, if appropriate, with one or more of the above-mentioned excipients.

Liquid dosage forms of the instant pharmaceutical compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethyl formamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.

Besides inert diluents, the oral pharmaceutical compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavouring, and perfuming agents.

Suspensions of the instant compounds, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminium metahydroxide, bentonite, agar-agar, and tragacanth, and mixtures thereof.

Pharmaceutical compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.

Dosage forms for topical administration of a compound or pharmaceutical composition of the present disclosure include powders, patches, sprays, ointments and inhalants. The active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives, buffers, or propellants which may be required.

Dosage forms for application to the eye include solutions, suspensions, ointments, gels, emulsions, strips, inserts such as contact lenses, and implants, which may be administered topically, intravitreally, perioccularly, and the like.

Uses

The present disclosure is directed to novel heterocyclic prolinamide derivatives of Formula I, and pharmaceutically acceptable salts, solvates, salts of solvates and prodrugs thereof, useful in the prevention (e.g., delaying the onset of or reducing the risk of developing) and treatment (e.g., controlling, alleviating, or slowing the progression of) of age-related macular degeneration (AMD) and related diseases of the eye. These diseases include dry-AMD, wet-AMD, geographic atrophy, diabetic retinopathy, retinopathy of prematurity, polypoidal choroidal vasculopathy, diabetic macula edema (DME), other retinopathies such as choroidal neovascularisation (CNV), choroidal neovascular membrane (CNVM), cystoid macular edema (CME), epi-retinal membrane (ERM) and macular hole, hypertrophic changes of the retinal pigment epithelium (RPE), atrophic changes of the retinal pigment epithelium, retinal detachment, choroidal vein occlusion, retinal vein occlusion, corneal angiogenesis following, for example, keratitis, cornea transplantation or keratoplasty, corneal angiogenesis due to hypoxia (e.g., induced by extensive contact lens wearing), pterygium conjunctivae, subretinal edema, intraretinal edema, Stargardt disease and degeneration of retinal or photoreceptor cells. The present disclosure disclosed herein is further directed to methods of prevention, slowing the progress of, and treatment of dry-AMD, wet-AMD, and geographic atrophy, diabetic retinopathy, retinopathy of prematurity, polypoidal choroidal vasculopathy, diabetic macula edema (DME), other retinopathies such as choroidal neovascularisation (CNV), choroidal neovascular membrane (CNVM), cystoid macular edema (CME), epi-retinal membrane (ERM) and macular hole, hypertrophic changes of the retinal pigment epithelium (RPE), atrophic changes of the retinal pigment epithelium, retinal detachment, choroidal vein occlusion, retinal vein occlusion, corneal angiogenesis following, for example, keratitis, cornea transplantation or keratoplasty, corneal angiogenesis due to hypoxia (e.g., induced by extensive contact lens wearing), pterygium conjunctivae, subretinal edema, intraretinal edema, Stargardt disease and degeneration of retinal or photoreceptor cells, comprising: administration of a therapeutically effective amount of compound of the present disclosure. The compounds of the present disclosure are inhibitors of HTRA1. Thus, the compounds of the present disclosure are useful in the prevention and treatment of a wide range diseases mediated (in whole or in part) by HTRA1. The compounds of the present disclosure are also useful for inhibiting HTRA1 protease activity in an eye and elsewhere. By virtue of their activity profile, the compounds of the present disclosure are particularly suitable for the treatment and/or prevention of ocular disorders, such as age-related macular degeneration (AMD) like wet-AMD or dry-AMD, geographic atrophy, diabetic retinopathy, Stargardt disease, choroidal neovascularisation (CNV), and diabetic macula edema (DME).

Additionally, compounds of the present disclosure may be useful in the treatment of other diseases in which HTRA1 may be involved, including retinal angiomatous proliferation, foveomacular proliferation, musculoskeletal diseases, including osteoarthritis, spinal disk degeneration rheumatoid arthritis, muscular dystrophy and osteoporosis, and treatment of autologous chondrocytes prior to intraarticular implantation.

Administration

The compounds and compositions described herein can, for example, be administered orally, parenterally (e.g., subcutaneously, intracutaneously, intravenously, intramuscularly, intraarticularly, intraarterially, intrasynovially, intrasternally, intrathecally, intralesionally and by intracranial injection or infusion techniques), by inhalation spray, topically, rectally, nasally, buccally, vaginally, via an implanted reservoir, by injection, subdermally, intraperitoneally, transmucosally, or in an ophthalmic preparation, with a dosage ranging from about 0.01 mg/kg to about 1000 mg/kg, (e.g., from about 0.01 to about 100 mg/kg, from about 0.1 to about 100 mg/kg, from about 1 to about 100 mg/kg, from about 1 to about 10 mg/kg) every 4 to 120 hours, or according to the requirements of the particular drug, dosage form, and/or route of administration. The interrelationship of dosages for animals and humans (based on milligrams per meter squared of body surface) is described by Freireich et al., Cancer Chemother. Rep. 50, 219-244 (1966). Body surface area may be approximately determined from height and weight of the patient. See, e.g., Scientific Tables, Geigy Pharmaceuticals, Ardsley, N.Y., 537 (1970). In certain embodiments, the compositions are administered by oral administration or by injection. The methods herein contemplate administration of an effective amount of compound or compound composition to achieve the desired or stated effect. Typically, the pharmaceutical compositions of the present disclosure will be administered from about 1 to about 6 times per day or alternatively, as a continuous infusion. Such administration can be used as a chronic or acute therapy.

Lower or higher doses than those recited above may be required. Specific dosage and treatment regimens for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health status, sex, diet, time of administration, rate of excretion, drug combination, the severity and course of the disease, condition or symptoms, the patient's disposition to the disease, and the judgment of the treating physician.

Dosage forms include from about 0.001 milligrams to about 2,000 milligrams (including, from about 0.001 milligrams to about 1,000 milligrams, from about 0.001 milligrams to about 500 milligrams, from about 0.01 milligrams to about 250 milligrams, from about 0.01 milligrams to about 100 milligrams, from about 0.05 milligrams to about 50 milligrams, and from about 0.1 milligrams to about 25 milligrams) of a compound of Formula I (and/or a compound of any of the other formulae described herein) or a salt (e.g., a pharmaceutically acceptable salt) thereof as defined anywhere herein. The dosage forms can further include a pharmaceutically acceptable carrier and/or an additional therapeutic agent.

With regard to ophthalmic preparation, because AMD and related diseases (including dry-AMD, Wet-AMD, geographic atrophy, diabetic retinopathy, retinopathy of prematurity, polypoidal choroidal vasculopathy, and degeneration of retinal or photoreceptor cells) primarily afflict the back of the eye, local administration such as topical administration, trans-scleral drug delivery and intravitreal administration may be preferable over systemic administration. Intravitreal administration can be further divided into intravitreal injection and intravitreal implants. Of these, intravitreal injection appears to be the most widely used. Products utilizing intravitreal injection include Trivaris® (triamcinolone acetonide), Triescence® (triamcinolone acetonide, Alcon Fort Worth, Tex.), Macugen® (pegaptanib sodium, Bausch and Lomb, Rochester, N.Y.), Lucentis® (ranibizumab injection, Genentech, South San Francisco, Calif.), Ozurdex® (dexamethasone, Allergan, Inc., Irvine, Calif.) and Iluvien® (flucinolone acetonide, Alimera Sciences, Alpharetta, Ga.). The preferred dosage range for local administration to the back of the eye ranges from 0.001 mg to 100 mg (including from about 0.01 milligrams to about 500 milligrams, from about 0.05 milligrams to about 250 milligrams, from about 0.05 milligrams to about 100 milligrams, from about 0.1 milligrams to about 50 milligrams, from about 0.1 milligrams to about 25 milligrams, and from about 0.1 milligrams to about 10 milligrams). References on the subject of ophthalmic drug delivery include:

-   Kompella U. B. et al., Recent Advances in Ophthalmic Drug Delivery,     Ther. Deliv. 2010 1(3): 435-456; -   Gaudana R. et al., Ocular Drug Delivery, AAPS Journal, Vol. 12, No.     3: 348-360 (2010); -   Haghjou N. et al., Sustained Release Intraocular Drug Delivery     Devices for Treatment of Uveitis, J. Ophthalmic Vis. Res. 2011; 6     (4): 317-329; -   Kuno N. and Fujii S. Recent Advances in Ocular Drug Delivery     Systems, Polymers (2011), 3:193-221; -   Patel A. et al., Ocular Drug Delivery Systems: An Overview, World J.     Pharmacol. (2013) 2:47-64; -   Morrison P. W. J. and Khutoryanskiy V. V. Advances in Ophthalmic     Drug Delivery, Ther. Deliv. (2014) 5:1297-1315; -   Chen H. Recent Developments in Ocular Drug Delivery, J. Drug Target     (2015), 23:597-604; all of which are incorporated by reference.

For the treatment and/or prevention of ocular disorders, as described above, the preferred route for administering the compounds of the present disclosure is topically at the eye or by an ocular drug delivery system. Intraocular injections are another way to administer the compounds of the present disclosure that is suitable for such purposes.

Delivery to areas within the eye can be accomplished by injection, employing a cannula or another invasive device designed to introduce precisely metered amounts of a desired formulation to a particular compartment or tissue within the eye (e.g., posterior chamber or retina). An intraocular injection may be into the vitreous (intravitreal), under the conjunctiva (subconjunctival), behind the eye (retrobulbar), into the sclera, or under the Capsule of Tenon (sub-Tenon), and may be in a depot form. Other intraocular routes of administration and injection sites and forms are also contemplated and are within the scope of the present disclosure.

The compounds according to the present disclosure may be formulated in a manner known to those skilled in the art so as to give adequate delivery to the back of the eye, which may be by regular dosing, such as with eye drops, or by using a delivery system to give a controlled release, such as slow release, of the compounds according to the present disclosure.

Preferred ocular formulations for the compounds of the present disclosure include aqueous solutions, suspensions or gels of these compounds in the form of drops of liquid, liquid washes, sprays, ointments or gels, in a mixture with excipients suitable for the manufacture and use of such application forms. Alternatively, the compounds of the present disclosure may be applied to the eye via liposomes or other ocular delivery systems that are known in the art.

Appropriate dosage levels may be determined by any suitable method known to one skilled in the art of treating eye diseases. Preferably, the active substance is administered at a frequency of 1 to 4 times per day for topical administration, or less often if a drug delivery system is used. Typically, an ocular formulation intended for topical application contains the active ingredient in a concentration range of about 0.0010% to 10%.

Nevertheless, actual dosage levels and time course of administration of the active ingredients in the pharmaceutical compositions of the present disclosure may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition and mode of administration, without being toxic to the patient. It may therefore be necessary where appropriate to deviate from the stated amounts, in particular as a function of age, gender, body weight, diet and general health status of the patient, route of administration, individual response to the active ingredient, nature of the preparation, and time or interval over which administration takes place. Thus, it may be satisfactory in some cases to manage with less than the aforementioned minimum amount, whereas in other cases the stated upper limit must be exceeded. It may in the event of administration of larger amounts be advisable to divide these into multiple individual doses spread over the day.

In one aspect the compounds of the present disclosure may be co-administered with one or more additional agents. The additional agents include, but are not limited to Acuvail® (ketorolac tromethamine ophthalmic solution), AK-Con-A®/OcuHist® (pheniramine maleate-naphazoline HCl, ophthalmic solution), Akten® (lidocaine HCl ophthalmic gel), Alamast® (pemirolast potassium ophthalmic solution), Alphagan® (brimonidine tartrate ophthalmic solution), Bepreve® (bepotastine besilate ophthalmic solution), Besivance® (besifloxacin ophthalmic suspension), Betaxon® (levobetaxolol HCl ophthalmic suspension), Cosopt® (dorzolamide HCl—timolol maleate, ophthalmic solution), Cystaran® (cysteamine HCl ophthalmic solution), Durezol® (difluprednate ophthalmic emulsion), Eylea® (aflibercept intravitreal injection), Jetrea® (ocriplasmin intravitreal injection), Lotemax® (loteprednol etabonate ophthalmic suspension), Lucentis® (ranibizumab injection), Lumigan® (bimatoprost ophthalmic solution), Macugen® (pegaptanib intravitreal injection), Ocuflox® (ofloxacin ophthalmic solution), Omidria® (phenylephrine and ketorolac injection), Ozurdex® (dexamethasone intravitreal implant), Quixin® (levofloxacin ophthalmic solution), Rescula® (unoprostone isopropyl ophthalmic solution 0.15%), Restasis® (cyclosporine ophthalmic emulsion), Salagen® (pilocarpine HCl tablets), Travatan® (travoprost ophthalmic solution), Valcyte® (valganciclovir HCl tablets and oral solution), Vistide® (cidofovir tablets), Visudyne® (verteporfin injection), Vitrasert® (ganciclovir implant), Vitravene® (fomivirsen injection), Zioptan® (tafluprost ophthalmic solution), Zirgan® (ganciclovir ophthalmic gel), and Zymaxid® (gatifloxacin ophthalmic solution). Furthermore the compounds of the disclosure may be co-administered with one or more inhibitors of VEGF-mediated angiogenesis, such as, for example, ACTB-1003 (Edding Pharm, CN), apatinib, axitinib, bevacizumab, bevasiranib, BMS-690514 (Bristol-Myers Squibb (BMS), NY), brivanib, cediranib, CT-322 (Adnexus/BMS, MA), dovitinib, lenvatinib, foretinib, KH-902/conbercept (approved in CN for exudative macular degeneration), linifanib, MGCD-265 (Mirati Therapeutics, CA), motesanib, elpamotide, pazopanib, pegaptanib, ranibizumab, regorafenib, ruboxystaurin, sorafenib, SU-14813 (Pfizer, CT), sunitinib, telatinib, TG-100801, tivozanib, TSU-68 (Taiho Pharmaceuticals, JP), vandetanib, vargatef, vatalanib and Carbometyx® (cabozantinib tablets, Exelixis, CA), or with inhibitors of other signaling pathways, such as disulfiram, fenretinide, mecamylamine, PF-04523655 (Pfizer, CT), sonepcizumab, tandospirone and volociximab.

Additional agents which may be utilized for co-administration include: known vitamins and antioxidants such as AREDS/AREDS2 (supplements used in Age-Related Eye Disease Study/Study 2, National Eye Institute, US), omega-3 fatty acids, lutein, zeaxanthin, vitamin A; visual-cycle modulators such as emixustat (ACU-4429, Acucela, WA); anti-inflammatory agents such as Illuvien® (fluocinolone acetonide), sirolimus, Triesence®/Trivaris® (triamcinolone acetonide); complement modulators such as lampalizumab, Soliris® (eculizumab, Alexion, CT); amyloid-modulators such as GSK933776 (GlaxosmithKline, PA), RN6G (PF-04382923, Pfizer, CT) and platelet-derived growth factor modulators such as, for example, Fovista® (pegpleranib, Ophthotech, NY).

In certain embodiments, the additional agents may be administered separately (e.g., sequentially; on different overlapping schedules), as part of a multiple dose regimen, from the compounds of the present disclosure (e.g., one or more compounds of Formula (I) and/or a compound of any of the other formulae, including any subgenera or specific compounds thereof). In other embodiments, these agents may be part of a single dosage form, mixed together with the compounds of the present disclosure in a single composition. In still another embodiment, these agents can be given as a separate dose that is administered at about the same time as that of one or more compounds of Formula (I) (and/or a compound of any of the other formulae, including any subgenera or specific compounds thereof) are administered (e.g., simultaneously with the administration of one or more compounds of Formula (I) (and/or a compound of any of the other formulae, including any subgenera or specific compounds thereof)). When the compositions of the present disclosure include a combination of a compound of the formulae described herein and one or more additional therapeutic or prophylactic agents, both the compound and the additional agent can be present at dosage levels of between about 1 to 100%, and more preferably between about 5 to 95% of the dosage normally administered in a monotherapy regimen.

The compositions of the present disclosure may contain any conventional non-toxic pharmaceutically-acceptable carriers, adjuvants or vehicles. In some cases, the pH of the formulation may be adjusted with pharmaceutically acceptable acids, bases or buffers to enhance the stability of the formulated compound or its delivery form.

The compositions of the present disclosure may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, emulsions and aqueous suspensions, dispersions and solutions. In the case of tablets for oral use, carriers which are commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions and/or emulsions are administered orally, the active ingredient may be suspended or dissolved in an oily phase and then combined with emulsifying and/or suspending agents. If desired, certain sweetening and/or flavoring and/or coloring agents may be added.

Biological Function

The utility of the present disclosure can be demonstrated by one or more of the following methods or other methods known in the art:

Full Length HTRA1 Assay

Serial dilutions (1/3) from 1000 μM down to 0.051 μM of test compounds were prepared in dimethyl sulfoxide (DMSO). Then 2 μL of solution from each dilution were added to 100 μL of 4 nM full-length human His-HTRA1 in assay buffer (50 mM Tris, pH 7.5, 200 mM NaCl and 0.25% 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate or CHAPS) in white non-binding 96-well plates. The assay solutions were mixed for 5 seconds on a shaker plate and incubated for 10 minutes at room temperature. Mca-H₂OPT (Mca-Ile-Arg-Arg-Val-Ser-Tyr-Ser-Phe-Lys(Dnp)-Lys-OH trifluoroacetate salt) (Mca=7-methoxycoumarin-4-acetic acid; Dnp=dinitrophenyl) (5 μM) in 100 μL of assay buffer was added to the assay solutions. The reaction mixture was shaken for 5 seconds on a shaker plate and cleavage of Mca-H₂OPT was monitored by spectrofluorometry (SpectraMax M3 by Molecular Devices, CA) for 10 minutes (Exλ=330 nm; Emλ=420 nm). Percent inhibition was calculated by fitting values to a standard mathematical model for determining the dose response curve.

Example HTRA1 IC₅₀ (μM) 1 0.34 2 0.014 3 0.070 4 0.016 5 0.095 6 0.10 7 0.051 8 0.076 9 0.066 10 0.044 11 0.062 12 0.014 13 0.038 14 0.006 15 0.005 16 0.017 17 0.086 18 0.033 19 0.036 20 0.23 21 0.50 22 0.10 23 0.063 24 0.010 25 0.014 26 0.074 27 0.25 28 0.042 29 0.025 30 0.014 31 0.029 32 0.13 33 0.045 34 0.10 35 0.081 36 0.019 37 0.037 38 0.051 39 0.008 40 0.039 41 0.042 42 0.025 43 0.038 44 0.023 45 0.016 46 0.12 47 0.18 48 0.031 49 0.017 50 0.023 51 0.018 52 0.018 53 0.045 54 0.020 55 0.025 56 0.017 57 0.32 58 0.050 59 0.081 60 0.17 61 0.075 62 0.47 63 0.095 64 0.22 65 0.29 66 0.21 67 0.51 68 0.091 69 0.25 70 0.12 71 0.23 72 0.013 73 0.010 74 0.009 75 0.004 76 0.005 77 0.009 78 0.056 79 0.007 80 0.011 81 0.007 82 0.007 83 0.005 84 0.019 85 0.016 86 0.019 87 0.009 88 0.004 89 0.008 90 0.012 91 0.009 92 0.005 93 0.004 94 0.009 95 0.005 96 0.006 97 0.006 98 0.005 99 0.005 100 0.006 101 0.006 102 0.006 103 0.004 104 0.009 105 0.009 106 0.006 107 0.004 108 0.007 109 0.008 110 0.004 111 0.003 112 0.004 113 0.004 114 0.004 115 0.008 116 0.004 117 0.009 118 0.005 119 0.015 120 0.010 121 0.007 122 0.012 123 0.020 124 0.009 125 0.017 126 0.014 127 0.008 128 0.017 129 0.009 130 0.038 131 0.010 132 0.008 133 0.008 134 0.009 135 0.008 136 0.005 137 0.012 138 0.006 139 0.009 140 0.006 141 0.009 142 0.009 143 0.011 144 0.008 145 0.033 146 0.014 147 0.020 148 0.057 149 0.028 150 0.78 151 0.028 152 0.086 153 0.030 154 0.030 155 0.020 156 0.03 157 0.023 158 0.13 159 0.055 160 0.071 161 0.039 162 0.11 163 0.068 164 0.032 165 0.207

Synthesis

The starting materials used for the synthesis are either synthesized or obtained from commercial sources, such as, but not limited to, Sigma-Aldrich, Fluka, Acros Organics, Alfa Aesar, Enamine, PharmaBlock, VWR Scientific, and the like. The reversed phase and normal phase chromatography columns were purchased from Teledyne ISCO, Inc. (NE), and the Isolute phase separators were purchased from Biotage (NC). Nuclear Magnetic Resonance (NMR) analysis was conducted using a Varian Mercury 300 MHz spectrometer with an appropriate deuterated solvent. LCMS analysis was conducted using a Waters Acquity UPLC with a QDA MS detector using a Waters C18 BEH 1.7 μM, 2.1×50 mm column, eluting with 95:5 to 0:100 H₂O:MeCN+0.1% formic acid at a flow rate of 0.6 mL/min over 3.5 minutes. The QDA MS detector was set up to scan under both positive and negative mode ions ranging from 100-1200 Daltons. General methods for the preparation of compounds can be modified by the use of appropriate reagents and conditions for the introduction of the various moieties found in the structures as provided herein.

Abbreviations

-   ACN acetonitrile -   aq. aqueous -   Bn benzyl -   BnNH₂ benzylamine -   Boc tert-butyloxycarbonyl -   Boc₂O di-tert-butyl dicarbonate -   C Celsius -   conc. concentrated -   Cp*RuCl(Ph₃P)₂     chloro(pentamethylcyclopentadienyl)bis(triphenylphosphine)ruthenium     (II) -   d days -   DCM dichloromethane or methylene chloride -   DEAD diethyl azodicarboxylate -   DIAD diisopropyl azodicarboxylate -   DMA dimethylacetamide -   DMF dimethylformamide -   DMP Dess-Martin periodinane -   DMSO dimethylsulfoxide -   EDC N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride -   Et ethyl -   EtOAc ethyl acetate -   Et₂O diethylether -   g gram -   h hour -   HATU     1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium     3-oxid hexafluorophosphate -   HOAt 1-hydroxy-7-azobenzotriazole -   IBX 2-iodoxybenzoic acid -   L liter -   LAH lithium aluminum hydride -   LC-MS liquid chromatography mass spectrometry -   M molar -   mCPBA meta-chloroperoxybenzoic acid -   MeOH methanol -   min minutes -   mg milligram -   mmol millimoles -   Ms methanesulfonyl -   MsCl methanesulfonyl chloride -   MTBE methyl t-butylether -   N normality -   PCy₃ HBF₄ tricyclohexylphosphine tetrafluoroborate -   Pd/C palladium on carbon -   iPr isopropyl -   iPr₂EtN or iPr₂NEt diisopropylethylamine or Hunig's base -   iPrOH isopropanol -   PyAOP (7-azabenzotriazol-1-yloxy)tripyrrolidinophosphonium     hexafluorophosphate -   sat. saturated -   TEA or Et₃N triethylamine -   THF tetrahydrofuran -   TLC thin layer chromatography -   μl microliter -   wt weight -   X-Phos G2     chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)

General Synthetic Scheme

In some embodiments, compounds described herein can be prepared as outlined in the following general synthetic schemes. These compounds may be viewed as consisting of four units as shown in the general structure: A—the R¹—Y group, B—an α-amino acyl group, C—the prolyl group, and D—an aminoheterocyclic group; and this shorthand notation is used below to refer to such units and the various combinations thereof. All the variables in the general structure and in the synthetic schemes are, unless otherwise specified, as defined in the claims; the triazole substituent R is a substituent for the heteroaryl group, as defined in the claims.

General Structure

Method I: Synthesis of Aminoheterocyclic 2-hydroxyacetamides (I-6, D)

The reduction of a suitably protected (e.g., Boc-protected) aminoheterocyclic carboxylic acid (I-1) to the corresponding alcohol (I-2) using a reducing agent such as LAH, followed by oxidation with, for example, DMP provides the aminoheterocyclic aldehyde (I-3). Alternatively, the protected aminoheterocyclic carboxylic acid (I-1) is coupled to N,O-dimethylhydroxylamine and the resulting N-methoxy-N-methylacetamide (I-7) is reduced, using for example LAH, to afford the corresponding aminoheterocyclic aldehyde (I-3). The aldehyde is treated with KCN and NaHSO₃ to give the desired cyanohydrin (I-4), which can then be hydrolyzed to the protected hydroxyacetamide (I-5) using standard basic conditions such as K₂CO₃/H₂O₂ or urea hydrogen peroxide/K₂CO₃ (similar to method as in Li, Yun-Long, et al., PCT Int. Appl. 2015191677, Dec. 17, 2015). The hydroxyacetamide (I-5) is then deprotected (e.g. using HCl for Boc) to provide the aminoheterocyclic 2-hydroxyacetamide (I-6, D). Alternatively, the cyanohydrins (I-4) can be hydrolyzed using conc. HCl to provide the deprotected aminoheterocyclic 2-hydroxyacetamide (I-6) in one step.

The hydroxyl amides containing cyclic ethers, cyclic sulfones or cyclic amides are oxidized to the corresponding ketoamides using a number of oxidative reagents such as DMP or IBX. The hydroxyamides containing a thio ether necessitate protection of the sulfide (e.g. via the addition of stoichiometric Pd/C or copper(II) acetate) to avoid oxidation of the thio ether to the corresponding sulfoxide.

Method II: Synthesis of 4-triazoloproline Intermediates (II-5, B-C)

The alcohol moiety of a protected 4-hydroxyproline ester (II-1) is converted to a mesylate with MsCl and then reacted with NaN₃ to afford 4-azidoproline (II-2). The azide intermediate is treated with substituted acetylenes in the presence of metal catalysis to afford the triazole adduct (II-3; see Boren, B. C., et a. J. Am. Chem. Soc. 2008, 130, 8923-8930 and Himo, F., et al. J. Am. Chem. Soc. 2005, 127, 210-216). Deprotection of the proline ring nitrogen, followed by coupling with another suitably protected amino acid using standard amide coupling conditions provides the triazoloproline (II-4). Hydrolysis of the ester under standard basic conditions such as LiOH affords the triazoloproline intermediate (II-5, B-C).

Method III: Synthesis of 4-triazoloproline Intermediates (III-3, A-B-C)

Alternatively, the azidoproline derivative (II-2) can be directly deprotected with HCl and then coupled with a suitably protected amino acid using standard amide coupling conditions to form the azidoproline intermediate (III-1). Deprotection with HCl followed by reaction with a carboxylic acid (or equivalent) using standard amide coupling conditions provides the N-acyl azidoproline intermediate (III-2). A [3+2] cycloaddition of this azide with a substituted acetylene using a metal catalysis as in Boren, B. C., supra, or Himo, F. supra, followed by hydrolysis under standard basic conditions such as LiOH gives the corresponding triazoloproline intermediate (III-3, A-B-C).

Method IV: Synthesis of Heterocyclic Ketoamides Intermediates (IV-3, B-C-D)

The protected B-C triazoloproline acid (II-5) is coupled with aminoheterocyclic 2-hydroxypropanamide (I-6, D) using standard amide coupling procedures to provide the protected hydroxyamide intermediate (IV-1). Oxidation of the hydroxyamide (IV-1) provides the corresponding ketoamide (IV-2). Hydroxyamides containing cyclic ethers, cyclic sulfones or cyclic amides can be oxidized to the corresponding ketoamides using an oxidative reagent such as DMP or IBX. For hydroxyamides containing a thioether, a stoichiometric amount of Pd/C or copper(II) acetate is added to avoid oxidation of the thioether to the corresponding sulfoxide. The Boc group can be deprotected using HCl to give the amino ketoamides (IV-3, B-C-D).

Method V: Synthesis of Product Ketoamides (V-1, B-C-D to A-B-C-D)

The B-C-D amino ketoamide (IV-3) can be coupled with carboxylic acid, acid chloride, sulfonyl chloride or isocyanate using standard procedures to form the amide linked, sulfonamide linked or urea linked ketoamide (V-1, A-B-C-D).

Method VI: Synthesis of Product Ketoamides (VI-2, A-B-C to A-B-C-D)

Triazoloproline carboxylic acid (III-3, A-B-C) can be coupled to the amino hydroxyamide (I-6, D) using standard amide coupling conditions to afford the corresponding hydroxyamide (VI-1), which can be oxidized as described in Method IV to afford the ketoamide (VI-2, A-B-C-D).

Method VII: Synthesis of Hydroxyprolines (VII-5, A-B-C-D)

4-Hydroxyproline methyl ester can be coupled with a protected amino acid using standard amide coupling procedures to provide the corresponding Boc protected hydroxyproline ester (VII-1, B-C). The protecting group can be cleaved using standard deprotection methods (e.g. for a Boc, deprotection can be accomplished via HCl) and the resulting amino ester can be reacted with acid chloride or carboxylic acid using standard conditions to afford the hydroxyproline esters (VII-2, A-B-C). The ester is hydrolyzed using basic protocols such as LiOH or NaOH in THF/MeOH to provide the carboxylic acid (VII-3), which is then coupled with aminoheterocyclic 2-hydroxyacetamide (I-6, D) to provide the hydroxyamide (VII-4). Oxidation of the hydroxyamide as described in Method IV provides the hydroxyproline ketoamide (VII-5, A-B-C-D).

Method VIII: Synthesis of Heterocyclic Substituted Prolines (VIII-1 and VIII-2, A-B-C-D)

The hydroxyproline ketoamides (VII-5) can be coupled with various heteroaromatics or hydroxyl heteroaromatics via standard Mitsunobu conditions such as DEAD/Ph₃P to provide the corresponding 4-heteroaromatic and heteroaromatic ether proline derivatives (VIII-1) and (VIII-2), respectively (A-B-C-D).

Method IX: Synthesis of Ketoproline Prolines (IX-1, A-B-C-D)

The hydroxyproline ketoamides (VII-5) can be oxidized using standard oxidation procedures such as DMP to provide the corresponding 4-ketoproline derivative (IX-1, A-B-C-D).

Method X: Synthesis of Aryl/Heteroaryl Prolines (X-3, A-B-C-D)

The ketoprolines (IX-1) is converted to the enol triflate (X-1) using triflic anhydride in the presence of base. This enol triflate can be coupled to form the aryl or heteroaryl proline (X-2) using standard cross-coupling conditions, such as palladium catalysis with the corresponding aryl or heteroaryl boronic acid. The resulting olefin can be selectively reduced using RhCl(PPh₃)₃ (Wilkinson's catalyst) to provide the aryl or heteroaryl proline derivative (X-3, A-B-C-D).

Method XI: Synthesis of Heterocyclic Boronic Acids (XI-5, A-B-C-D)

The sulfonamides (XI-1) can be prepared from the corresponding ketone using the method of Nitta, A., et al. Bioorg. Med. Chem. Lett. 2008, 18, 5435. This sulfonamide is converted to the corresponding boronate ester (XI-2) using the method of Ellman, J., et al. J. Org. Chem. 2014, 79, 3671. The sulfonamide group is deprotected using standard procedures such as HCl to afford the amino boronate ester (XI-3). The amino boronate is coupled to a carboxylic acid (A-B-C-OH) using standard amide coupling procedures to afford the fully elaborated boronate ester (XI-4). Deprotection of the boronate ester using standard acidic methods such as HCl/isobutane boronic acid gives the corresponding boronic acid (XI-5, A-B-C-D).

Preparation of Intermediates Intermediate A: benzyl 4-amino-4-(2-amino-1-hydroxy-2-oxoethyl)piperidine-1-carboxylate Hydrochloride

Step 1: Preparation of benzyl 4-((tert-butoxycarbonyl)amino)-4-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate (1)

To a solution of 1-((benzyloxy)carbonyl)-4-((tert-butoxycarbonyl)amino)piperidine-4-carboxylic acid (AstaTech, PA, catalog #66729) (4.5 g, 11.9 mmol) in DMA (22 mL) was added EDC (3.4 g, 17.8 mmol), HOAt (0.6 M in DMF, 3.96 mL, 2.38 mmol), N,O-dimethyl hydroxylamine hydrochloride (2.32 g, 23.8 mmol) and diisopropylethylamine (6.2 mL, 35.7 mmol). The reaction mixture was stirred at 35° C. for 3 hours at which point additional quantities of diisopropylethylamine (3.1 mL, 17.9 mmol), and EDC (152 mg, 0.79 mmol) were added and the mixture was stirred at 35° C. for an additional 2 hours. The mixture was then diluted with water (100 mL) and sat. aq. NH₄Cl (100 mL) and extracted with EtOAc (2×200 mL). The combined extracts were washed with sat. aq. NaHCO₃ (50 mL) and concentrated under reduced pressure. The resulting residue was purified by column chromatography using a RediSep cartridge (120 g, silica gel) eluting with a 0-60% EtOAc in hexanes gradient. The fractions were monitored by TLC using EtOAc/DCM (3/7). The desired fractions were concentrated under reduced pressure to give the title compound.

Step 2: Preparation of benzyl 4-((tert-butoxycarbonyl)amino)-4-formylpiperidine-1-carboxylate (2)

To a 250 mL round bottom flask charged with LAH (275 mg, 7.24 mmol) was added THF (30 mL) and the suspension was cooled to −78° C. in a dry ice/acetone bath for 5 minutes. This suspension was treated with a solution of compound 1 (3.05 g, 7.24 mmol) in THF (60 mL) via an addition funnel and the resulting mixture was stirred at −78° C. After 2 hours, the reaction mixture was quenched with a solution of 10% aq. NaHSO₄ hydrate (22 mL) dropwise over a period of 10 minutes. The cooling bath was removed and the mixture was stirred at 23° C. After 14 hours, the mixture was concentrated under reduced pressure and the resulting aqueous mixture was extracted with Et₂O (2×100 mL). The combined extracts were washed with 0.1 N HCl (100 mL) and then sat. aq. NaHCO₃ (50 mL). This solution was dried over MgSO₄, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography using a RediSep cartridge (120 g, silica gel) eluting with a 0-100% EtOAc in hexanes gradient. The desired fractions were concentrated under reduced pressure to provide the title compound.

Step 3: Preparation of benzyl 4-((tert-butoxycarbonyl)amino)-4-(cyano(hydroxy)methyl) piperidine-1-carboxylate (3)

To a solution of compound 2 (2.31 g, 6.38 mmol) in dioxane (24 mL) cooled to 0° C. in an ice bath was added 40% aq. NaHSO₃ (6.07 mL, 23.6 mmol) over a period of 10 minutes. The stirring was continued for an additional 10 minutes and the resulting mixture was treated with a solution of KCN (1.54 g, 23.6 mmol) in water (8.7 mL). This mixture was stirred for an additional 30 minutes and then the cooling bath was removed and the mixture was stirred at 23° C. After 2 hours, the mixture was extracted with EtOAc (100+75 mL). The combined extracts were washed with sat. aq. NaHCO₃, dried over MgSO₄, filtered and concentrated under reduced pressure to provide the title compound.

Step 4: Preparation of benzyl 4-(2-amino-1-hydroxy-2-oxoethyl)-4-(tert-butoxycarbonyl)amino)piperidine-1-carboxylate (4)

To a solution of compound 3 (1.0 g, 2.57 mmol) in DMSO (8 mL) and water (2.5 mL) cooled to 0° C. in an ice bath was added K₂CO₃ (177 mg, 1.28 mmol) and the mixture was stirred for 10 minutes. To this mixture was added urea hydrogen peroxide (1.21 g, 12.85 mmol) portionwise over 15 minutes. This mixture was stirred at 0° C. for another 10 minutes and then warmed to 23° C. After 6 hours, the mixture was diluted with water (50 mL) and extracted with EtOAc (2×50 mL). The combined extracts were washed with 10% aq. Na₂S₂O₃ (10 mL) and then brine (20 mL). The organic layer was dried over MgSO₄, filtered and concentrated under reduced pressure. This oil was purified by column chromatography using a RediSep cartridge (400 g, silica gel) eluting with a 0-10% MeOH in DCM gradient. The desired fractions were concentrated under reduced pressure to provide the title compound.

Step 5: Preparation of benzyl 4-amino-4-(2-amino-1-hydroxy-2-oxoethyl)piperidine-1-carboxylate Hydrochloride

To a solution of compound 4 (200 mg, 0.49 mmol) in MeOH (2 mL) was added 4 M HCl in dioxane (2 mL, 8 mmol) and the mixture was allowed to stand at 23° C. After 1 hour, the mixture was concentrated under reduced pressure to provide the title compound.

Intermediate B: 2-(4-aminotetrahydro-2H-pyran-4-yl)-2-hydroxyacetamide

Step 1: Preparation of tert-butyl (4-formyltetrahydro-2H-pyran-4-yl)carbamate (5)

To a solution of tert-butyl (4-(hydroxymethyl)tetrahydro-2H-pyran-4-yl)carbamate (PharmaBlock, CN, catalog #PBU0380) (8.0 g, 34.6 mmol) in DCM (100 mL) under nitrogen and cooled to 0° C. in an ice bath was added Dess-Martin periodinane (16.1 g, 38 mmol) and NaHCO₃ (4.4 g, 51.9 mmol). The resulting white suspension was stirred at 0° C. The reaction was monitored by TLC (hexanes/EtOAc 8:2) and after 1.5 hours was quenched with sat. aq. Na₂S₂O₃ (100 mL) and stirred at 23° C. After 1 hour, the white solid was filtered through celite and the filter pad was washed with DCM (2×50 mL). The filtrates were partitioned and the organic layer was dried over MgSO₄, filtered and concentrated under reduced pressure to provide the title compound.

Step 2: Preparation of tert-butyl (4-(cyano(hydroxy)methyl)tetrahydro-2H-pyran-4-yl)carbamate (6)

A solution of compound 5 (34.6 mmol) in dioxane (80 mL) was cooled to 0° C. in an ice bath and KCN (4.5 g, 69 mmol) was added followed by 40% aq. NaHSO₃ (18 mL, 69 mmol). After stirring at 0° C. for 1 hour, the cooling bath was removed and the reaction was allowed to stir at 23° C. After 18 hours, the mixture was diluted with water (100 mL) and extracted with EtOAc (3×75 mL). The combined extracts were washed with brine (75 mL), dried over MgSO₄, filtered and concentrated under reduced pressure. This residue was purified by column chromatography using a RediSep cartridge (120 g, silica gel) eluting with a 5-60% EtOAc in hexanes gradient. The desired fractions were concentrated under reduced pressure to provide the title compound as a white solid.

Step 3: Preparation of 2-(4-aminotetrahydro-2H-pyran-4-yl)-2-hydroxyacetamide

To a solution of compound 6 (3.80 g, 17.8 mmol) in dioxane (10 mL) was added 4 M HCl in dioxane (20 mL, 80 mmol) and the reaction mixture was stirred at 23° C. After 18 hours, the mixture was concentrated under reduced pressure and the residue was dried under high vacuum to provide the Boc deprotected crude intermediate. This yellow solid was dissolved in conc. HCl (50 mL) and stirred at 23° C. The reaction was monitored by LC-MS. After 6 hours, the mixture was concentrated under reduced pressure and the residue was further azeotroped with MeOH to remove residual water and HCl. This residue was dissolved in MeOH (10 mL) and treated with 1 M aq. NaOH to pH >10. The reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography using a RediSep cartridge (100 g, silica gel) eluting with a 0-25% MeOH in DCM gradient containing 0.1% TEA. The fractions were monitored by TLC using MeOH:DCM (8:2) visualized by KMnO₄ stain. The desired fractions were concentrated under reduced pressure to provide the title compound as a white foam.

Intermediate C: 2-(3-aminotetrahydrofuran-3-yl)-2-hydroxyacetamide Hydrochloride

Step 1: Preparation of tert-butyl (3-formyltetrahydrofuran-3-yl)carbamate (7)

The title compound was prepared in a similar manner to compound 5 using tert-butyl (3-(hydroxymethyl)tetrahydrofuran-3-yl)carbamate (PharmaBlock catalog #PB05450).

Step 2: Preparation of tert-butyl (3-(cyano(hydroxy)methyl)tetrahydrofuran-3-yl)carbamate (8)

The title compound was prepared in a similar manner to compound 6 using compound 7.

Step 3: Preparation of tert-butyl (3-(2-amino-1-hydroxy-2-oxoethyl)tetrahydrofuran-3-yl)carbamate (9)

The title compound was prepared in a similar manner to compound 4 using compound 8.

Step 4: Preparation of 2-(3-aminotetrahydrofuran-3-yl)-2-hydroxyacetamide Hydrochloride

The title compound was prepared in a similar manner to Intermediate A using compound 9.

Intermediate D: 2-(4-aminooxepan-4-yl)-2-hydroxyacetamide Hydrochloride

Step 1: Preparation of tert-butyl (4-(hydroxymethyl)oxepan-4-yl)carbamate (10)

To a solution of (4-aminooxepan-4-yl)methanol hydrochloride (Enamine catalog #2015-0049381A) (1.1 g, 6.06 mmol) in DMF (7 mL) was added Boc₂O (1.6 g, 7.27 mmol) and TEA (1.7 mL, 12.1 mmol) and the reaction mixture was stirred at 23° C. After 2 hours, the mixture was treated with imidazole (50 mg) to quench residual anhydride and then partitioned between water (20 mL) and EtOAc (20 mL). The aqueous layer was extracted with EtOAc (20 mL). The combined organic extracts were washed with 1 M HCl (20 mL), dried over MgSO₄, filtered and concentrated under reduced pressure to provide the title compound.

Steps 2-5: Preparation of 2-(4-aminooxepan-4-yl)-2-hydroxyacetamide Hydrochloride

The title compound was prepared in a similar manner to Intermediate C using compound 10.

Intermediate E: 2-(4-aminotetrahydro-2H-thiopyran-4-yl)-2-hydroxyacetamide

Step 1: Preparation of tert-butyl (4-(methoxy(methyl)carbamoyl)tetrahydro-2H-thiopyran-4-yl)carbamate (14)

To a solution of 4-((tert-butoxycarbonyl)amino)tetrahydro-2H-thiopyran-4-carboxylic acid (Oakwood Products, SC, catalog #300359) (20.5 g, 78.5 mmol) in DMA (200 mL) was added HATU (35.8 g, 94.1 mmol) and the reaction mixture was stirred at 23° C. After 5 minutes, the mixture was cooled to 0° C. in an ice bath and treated with iPr₂EtN (13.7 mL, 78.5 mmol) and stirred for 5 minutes. After this time, N,O-dimethyl hydroxylamine hydrochloride (15.3 g, 157 mmol) and additional iPr₂EtN (27.3 mL, 157 mmol) were added and the reaction mixture was stirred at 23° C. After 20 hours, water (500 mL) was added and the mixture was extracted with EtOAc (2×500 mL). The combined extracts were washed with 1 M aq. HCl (100 mL) and then sat. aq. NaHCO₃ (200 mL), dried over MgSO₄, filtered and concentrated under reduced pressure. This residue was purified by column chromatography using a RediSep cartridge (330 g, silica gel) eluting with a 0-100% EtOAc in hexanes gradient. The fractions were monitored by TLC (EtOAc:hexanes 1:1 visualized by KMnO₄). The desired fractions were concentrated under reduced pressure to provide the title compound as a white solid.

Step 2: Preparation of tert-butyl (4-formyltetrahydro-2H-thiopyran-4-yl)carbamate (15)

To a solution of compound 14 (3.05 g, 7.24 mmol) in THF (200 mL) cooled to −78° C. in a dry ice/acetone bath was added LAH (1.41 g, 37.1 mmol) portionwise over a period of 10 minutes. After the addition was complete, the dry ice/acetone bath was removed and the mixture was stirred at 0° C. in an ice bath. After 30 minutes, the mixture was cooled to −78° C. in a dry ice/acetone bath and a solution of NaHSO₃.H₂O (5.12 g, 37.1 mmol) in water (36.9 mL) was carefully added at such a rate to maintain the internal temperature below −50° C. After the addition was complete, the dry ice/acetone bath was exchanged for an ice bath and the mixture was stirred for 20 minutes followed by removal of the ice bath and stirring at 23° C. for 30 minutes. To this suspension was added Et₂O (200 mL) and the stirring was continued. After 20 minutes, this suspension was filtered through celite and the plug was washed with EtOAc (200 mL). The combined filtrates were washed with brine (50 mL), dried over MgSO₄, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography using a RediSep cartridge (120 g, silica gel) eluting with a 0-100% EtOAc in hexanes gradient. The desired fractions were concentrated under reduced pressure to provide the title compound.

Step 3: Preparation of tert-butyl (4-(cyano(hydroxy)methyl)tetrahydro-2H-thiopyran-4-yl)carbamate (16)

To a solution of compound 15 (5.39 g, 22.0 mmol) in dioxane (65 mL) cooled to 0° C. in an ice bath for 3 minutes was added a solution of 40% aq. NaHSO₄.H₂O (22.6 mL, 87.9 mmol) and the solution was stirred for 15 minutes. To this mixture was added a solution of KCN (5.7 g, 87.9 mmol) in water (33 mL) and the mixture was stirred at 0° C. for 10 minutes and then at 23° C. for 18 hours. This solution was partitioned between EtOAc (40 mL) and brine (40 mL) and the aqueous layer was extracted with EtOAc (100 mL). The combined extracts were dried over MgSO₄, filtered and concentrated under reduced pressure to provide the title compound.

Step 4: Preparation of 2-(4-aminotetrahydro-2H-thiopyran-4-yl)-2-hydroxyacetamide

The title compound was prepared in a similar manner as Intermediate B, step 3 using compound 16 (6.79 g, 22 mmol), and obtained as a white solid.

Intermediate F: 2-(3-aminotetrahydrothiophen-3-yl)-2-hydroxyacetamide

Step 1: Preparation of 3-((tert-butoxycarbonyl)amino)tetrahydrothiophene-3-carboxylic Acid (17)

To a solution of 3-aminotetrahydrothiophene-3-carboxylic acid hydrochloride (J&W PharmLab, PA, catalog #78301265) (3.0 g, 16.3 mmol) in dioxane (150 mL) was added 1 M aq. NaOH (48.9 mL, 48.9 mmol) and Boc₂O (7.13 g, 32.6 mmol) and the reaction mixture was stirred at 23° C. After 3 days, the mixture was acidified (pH=1-2) with 1 M aq. HCl (50 mL, 50 mmol) and extracted with EtOAc (2×100 mL). The combined extracts were concentrated under reduced pressure and purified by column chromatography using a RediSep cartridge (40 g, silica gel) eluting with a 20-100% EtOAc in hexanes gradient. The desired fractions were concentrated under reduced pressure to provide the title compound as a white solid.

Steps 2-5: Preparation of 2-(3-aminotetrahydrothiophen-3-yl)-2-hydroxyacetamide

The title compound was prepared in a similar manner to Intermediate E, steps 1-4, starting with compound 17.

Intermediate G: 2-(3-aminotetrahydro-2H-thiopyran-3-yl)-2-hydroxyacetamide Hydrochloride

Step 1: Preparation of 3-((tert-butoxycarbonyl)amino)tetrahydro-2H-thiopyran-3-carboxylic acid (21)

The title compound was prepared in a similar manner to compound 10 using 3-aminotetrahydro-2H-thiopyran-3-carboxylic acid hydrochloride.

Step 2: Preparation of tert-butyl (3-(methoxy(methyl)carbamoyl)tetrahydro-2H-thiopyran-3-yl)carbamate (22)

The title compound was prepared in a similar manner to compound 14 using compound 21.

Step 3: Preparation of tert-butyl(3-formyltetrahydro-2H-thiopyran-3-yl)carbamate (23)

The title compound was prepared in a similar manner to compound 15 using compound 22.

Step 4: Preparation of tert-butyl (3-(cyano(hydroxy)methyl)tetrahydro-2H-thiopyran-3-yl)carbamate (24)

The compound was prepared in similar manner to compound 16 using compound 23.

Step 5: Preparation of tert-butyl (3-(2-amino-1-hydroxy-2-oxoethyl)tetrahydro-2H-thiopyran-3-yl)carbamate (25)

The title compound was prepared in a similar manner to compound 4 using compound 24.

Step 6: Preparation of 2-(3-aminotetrahydro-2H-thiopyran-3-yl)-2-hydroxyacetamide Hydrochloride

The title compound was prepared in a similar manner to Intermediate A, step 5, using compound 25.

Intermediate H: (2S,4S)-1-((R)-2-((tert-butoxycarbonyl)amino)-3-cyclohexylpropanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxylic Acid

Step 1: Preparation of 1-(tert-butyl) 2-methyl (2S,4R)-4-((methylsulfonyl)oxy) pyrrolidine-1,2-dicarboxylate (26)

Into a 2 L round-bottom flask equipped with a large stir bar and under nitrogen was added 1-(tert-butyl) 2-methyl (2S,4R)-4-hydroxypyrrolidine-1,2-dicarboxylate (100.0 g, 0.4 mol) and DCM (800 mL). The solution was cooled to 0° C. in an ice bath and triethylamine (182 g, 1.8 mol) was added in a single portion, followed by drop-wise addition of methanesulfonyl chloride (103 g, 0.9 mol). The resulting mixture was stirred at 0° C. for 1 hour and then warmed to 23° C. and stirred for 18 hours. TLC analysis revealed complete conversion of the alcohol starting material. The reaction was quenched by pouring the mixture into water (2.0 L) and the mixture was extracted with DCM (3×1.0 L). The combined organic extracts were washed with sat. aq. NaHCO₃ (1.0 L), water (1.0 L) and brine (1.0 L), dried over MgSO₄, filtered and concentrated under reduced pressure to afford the title compound. This yellow oil (130 g) was used directly in the next step without further purification.

Step 2: Preparation of 1-(tert-butyl) 2-methyl (2S,4S)-4-azidopyrrolidine-1,2-dicarboxylate (27)

Into a 3 L round-bottom flask equipped with a magnetic stir bar and under nitrogen was added compound 26 (143 g, 442 mmol), sodium azide (53 g, 804 mmol) and DMF (900 mL). The solution was heated to 70° C. for 18 hours. The reaction mixture was cooled to 23° C. and poured into water (2.0 L) and extracted with MTBE (3×1 L). The combined organic extracts were washed with water (5×1.0 L), brine (2×1.0 L), dried over MgSO₄, filtered and concentrated under reduced pressure to afford the title compound as an oil (98 g).

Step 3: Preparation of 1-(tert-butyl) 2-methyl (2S,4S)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-1,2-dicarboxylate (28)

A solution of compound 27 (43 mL, 440 mmol, 2.0 equiv), Cp*RuCl(PPh₃)₂ (Strem catalog #44-0117) (8.8 g, 11 mmol, 0.05 equiv) and 1,4-dioxane (500 mL) were charged into a 1 L round-bottom flask. The solution was bubbled with a steady flow of nitrogen for 1 hour, and the reaction mixture changed color from yellow to deep brown. The reaction mixture was heated to 70° C. for 15 hours and then cooled to 23° C. The mixture was concentrated under reduced pressure to remove the bulk of the dioxane and the resulting oil was loaded directly onto a silica gel column (1 kg) and purified by column chromatography, eluting with a 2-4% MeOH in DCM gradient to afford the title compound as a brown oil (67 g).

Step 4: Preparation of methyl (2S,4S)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxylate Hydrochloride (29)

Compound 28 (98 g, 277 mmol), MeOH (400 mL) and methanolic HCl solution (approx. 3.0 M, 800 mL) were added to a 3 L round-bottom flask equipped with a magnetic stir bar. The reaction mixture was stirred at 23° C. for 12 hours at which point TLC analysis revealed complete conversion of starting material. The reaction mixture was concentrated under reduced pressure and dried under vacuum to remove any trace methanol or HCl residues. The resulting brown solid was used directly in the next step without further purification (90 g).

Step 5: Preparation of methyl (2S,4S)-1-((R)-2-((tert-butoxycarbonyl)amino)-3-cyclohexylpropanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxylate (30)

Into a 3 L round-bottom flask equipped with a magnetic stir bar was added compound 29 (70 g, 241 mmol), (R)-2-((tert-butoxycarbonyl)amino)-3-cyclohexylpropanoic acid (70 g, 258 mmol), HATU (110 g, 289 mmol), DCM (600 mL) and DMF (400 mL). The reaction mixture was treated with iPr₂EtN (126 g, 973 mmol) dropwise over 30 minutes and the mixture was stirred at 23° C. for 12 hours affording a deep brown solution. The reaction mixture was diluted with EtOAc (1.0 L) and washed with 1 M aq. HCl (3×400 mL), brine (3×300 mL), dried over Na₂SO₄ and concentrated under reduced pressure to afford an oil. The residue was purified by column chromatography through silica gel (1 kg), eluting with a 2-4% MeOH in DCM gradient to afford the title compound as a light brown solid (77 g).

Step 6: Preparation of (2S,4S)-1-((R)-2-((tert-butoxycarbonyl)amino)-3-cyclohexylpropanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxylic Acid

To a mixture of compound 30 (10.9 g, 21.5 mmol) in THE (43 mL) and MeOH (23 mL) was added 1 M aq. LiOH (87 mL, 86 mmol) and the reaction mixture was stirred at 23° C. for 1.5 hours. This mixture was treated with 1 M aq. HCl (86 mL) and concentrated under reduced pressure to provide the title compound.

Intermediate I: (2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxylic Acid

Step 1: Preparation of 1-(tert-butyl) 2-methyl (2S,4R)-4-((methylsulfonyl)oxy) pyrrolidine-1,2-dicarboxylate (31)

To a solution of 1-(tert-butyl) 2-methyl (2S,4R)-4-hydroxypyrrolidine-1,2-dicarboxylate (13.2 g, 53.8 mmol) in DCM (110 mL) cooled to 0° C. in an ice bath was added TEA (17 mL, 236.8 mmol) and MsCl (9.2 mL, 118.4 mmol). The reaction was allowed to warm to 23° C. and stirred for 18 hours. After this time, the reaction mixture was diluted with DCM and washed with aq. NaHCO₃, water and brine. The organic layer was dried over MgSO₄, filtered and concentrated under reduced pressure to provide the title compound.

Step 2: Preparation (2S,4S)-1-tert-butyl 2-methyl 4-azidopyrrolidine-1,2-dicarboxylate (32)

A suspension of compound 31 (20 g, 53.8 mmol) and NaN₃ (7.0 g, 107.6 mmol) in DMF (110 mL) was stirred at 75° C. After 24 hours, the mixture was allowed to cool to 23° C. and diluted with water and extracted with EtOAc (3×100 mL). The combined extracts were washed with brine, dried over MgSO₄, filtered and concentrated under reduced pressure. This residue was purified by column chromatography using a RediSep cartridge (80 g, silica gel) eluting with a 0-20% EtOAc in hexanes gradient. The desired fractions were concentrated under reduced pressure to provide the title compound.

Step 3: Preparation of methyl (2S,4S)-4-azidopyrrolidine-2-carboxylate Hydrochloride (33)

To a solution of compound 32 (14.5 g, 53.8 mmol) in MeOH (135 mL) was added 36% aq. HCl (19 mL, 188.3 mmol) and the reaction mixture was stirred at 23° C. After 18 hours, the mixture was concentrated under reduced pressure and the residue azeotroped with MeOH (3×50 mL) to provide the title compound.

Step 4: Preparation of methyl (2S,4S)-4-azido-1-((R)-2-((tert-butoxycarbonyl)amino)-3-cyclohexylpropanoyl)pyrrolidine-2-carboxylate (34)

A suspension of compound 33 (12.8 g, 47 mmol) and HATU (17.9 g, 47 mmol) in DCM (110 mL) was stirred for 10 minutes and then methyl (2S,4S)-4-azidopyrrolidine-2-carboxylate hydrochloride (9.73 g, 47 mmol) and iPr₂EtN (20.5 mL, 118 mmol) were added and the reaction mixture was stirred at 23° C. After 18 hours, the mixture was partitioned with 1 M aq. HCl (200 mL). The aqueous layer was extracted with DCM (3×100 mL). The combined organic extracts were washed with brine, dried over MgSO₄, filtered and concentrated under reduced pressure. This residue was purified by column chromatography using a RediSep cartridge (120 g, silica gel) eluting with a 0-50% EtOAc in hexanes gradient. The fractions were monitored by TLC (EtOAc/hexanes (3/7) visualized by ninhydrin staining). The desired fractions were concentrated under reduced pressure to provide the title compound.

Step 5: Preparation of methyl (2S,4S)-1-((R)-2-amino-3-cyclohexylpropanoyl)-4-azidopyrrolidine-2-carboxylate Hydrochloride (35)

The title compound was prepared in a similar manner as compound 29 using compound 34.

Step 6: Preparation of methyl (2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4-azidopyrrolidine-2-carboxylate (36)

To a suspension of compound 35 (10.4 g, 29 mmol) and 2-naphthoyl chloride (6.1 g, 31.9 mmol) in DCM (150 mL) was added iPr₂EtN (12.6 mL, 72.5 mmol) and the reaction mixture was stirred at 23° C. After 6 hours, the mixture was partitioned between 1 M aq. HCl (100 mL) and DCM (100 mL). The aqueous layer was extracted with DCM (2×100 mL). The combined extracts were washed with water, dried over MgSO₄, filtered and concentrated under reduced pressure. This residue was purified by column chromatography using a RediSep cartridge (330 g, silica gel) eluting with a 0-50% EtOAc in hexanes gradient. The desired fractions were concentrated under reduced pressure to provide the title compound.

Step 7: Preparation of methyl (2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxylate (37)

To a 40 mL scintillation vial was added compound 36 (2.5 g, 5.2 mmol), 2-methylbut-3-yn-2-ol (1.74 g, 20.8 mmol), pentamethylcyclopentadienylbis(triphenylphosphine)ruthenium(II) chloride (199 mg, 0.26 mmol) and dioxane (26 mL). This mixture was stirred at 64° C. under nitrogen for 3 hours. After this time, this mixture was purified by column chromatography using a RediSep cartridge (40 g, silica gel) eluting with EtOAc. The desired fractions were concentrated under reduced pressure to provide the title compound.

Step 8: Preparation of (2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxylic Acid

To a solution of compound 37 (2.9 g, 5.3 mmol) in MeOH (25 mL) and THF (25 mL) was added 1 M aq. LiOH (26 mL, 26 mmol) and the mixture was stirred at 23° C. After 1 hour, the mixture was concentrated under reduced pressure and the resulting residue was dissolved in THF (30 mL) and acidified to pH=1 with 1 M aq. HCl. This mixture was further diluted with water and extracted with EtOAc (3×20 mL). The combined extracts were dried over MgSO₄, filtered and concentrated under reduced pressure to provide the title compound.

Intermediate J: (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-2-amino-3-cyclohexylpropanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide Hydrochloride

Step 1: Preparation of tert-butyl (2R)-1-((2S,4S)-2-((4-(2-amino-1-hydroxy-2-oxoethyl)tetrahydro-2H-pyran-4-yl)carbamoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidin-1-yl)-3-cyclohexyl-1-oxopropan-2-yl)carbamate (38)

To a suspension of (2S,4S)-1-((R)-2-((tert-butoxycarbonyl)amino)-3-cyclohexylpropanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxylic acid (Intermediate H, 21.7 g, 44 mmol) and HATU (20 g, 53 mmol) in DCM (220 mL) was added Intermediate B (10.2 g, 48.4 mmol) and iPr₂EtN (34.5 mL, 198 mmol) and the yellow solution was stirred at 23° C. After 18 hours, sat. aq. NaHCO₃ was added and the aqueous layer was extracted with DCM (4×100 mL). The combined extracts were dried over MgSO₄, filtered and concentrated under reduced pressure. The residue was purified by column chromatography using a RediSep cartridge (330 g, silica gel) eluting with a 0-15% MeOH in DCM gradient. The desired fractions were concentrated under reduced pressure to provide the title compound as a white solid.

Step 2: Preparation of tert-butyl ((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)carbamoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidin-1-yl)-3-cyclohexyl-1-oxopropan-2-yl)carbamate (39)

To a solution of compound 38 (7.5 g, 11.6 mmol) in DMSO (60 mL) was added IBX (45% by weight, 14.4 g, 23.1 mmol) and the reaction mixture was stirred at 23° C. After 6 hours, additional IBX (2.1 g, 3.4 mmol) was added and the reaction mixture was stirred at 23° C. for a further 18 hours. The mixture was quenched with 10% aq. Na₂S₂O₃ (65 mL, 17.4 mmol) and extracted with EtOAc (3×50 mL). The combined extracts were washed with sat. aq. NaHCO₃, brine (1×), dried, filtered and concentrated under reduced pressure. This residue was purified by column chromatography using a RediSep cartridge (330 g, silica gel) eluting with a 0-7.5% MeOH in DCM gradient. The desired fractions were concentrated under reduced pressure to provide the title compound as a white solid.

Step 3: Preparation of (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-2-amino-3-cyclohexylpropanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide Hydrochloride

To a solution of compound 39 (3.45 g, 5.33 mmol) in MeOH (27 mL) was added 36% aq. HCl (2.6 mL, 26.7 mmol) and the mixture was stirred at 23° C. After 18 hours, the mixture was concentrated under reduced pressure to provide the title compound.

Intermediate K: (2S,4S)—N-(4-(2-amino-2-oxoacetyl)oxepan-4-yl)-1-((R)-2-amino-3-cyclohexylpropanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide Hydrochloride

The title compound was prepared in a similar manner to Intermediate J using Intermediate D.

Intermediate L: (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)-1-((R)-2-amino-3-cyclohexylpropanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide Hydrochloride

Step 1: Preparation of tert-butyl ((2R)-1-((2S,4S)-2-((4-(2-amino-1-hydroxy-2-oxoethyl)tetrahydro-2H-thiopyran-4-yl)carbamoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidin-1-yl)-3-cyclohexyl-1-oxopropan-2-yl)carbamate (42)

The title compound was prepared in a similar manner to compound 38 using Intermediate E, where DMF was used in place of DCM as the solvent.

Step 2: Preparation of tert-butyl ((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)carbamoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidin-1-yl)-3-cyclohexyl-1-oxopropan-2-yl)carbamate (43)

To a solution of compound 42 (5.0 g, 7.51 mmol) in DCM (150 mL) was added copper (II) acetate hydrate (0.75 g, 3.75 mmol) and the reaction mixture was stirred at 23° C. for 30 minutes. DMP (3.82 g, 9.0 mmol) was added and the reaction mixture was stirred at 23° C. The reaction was monitored by LC-MS and additional DMP (3.82 g, 9.0 mmol) was added portionwise. After 4 hours, the reaction mixture was washed with 10% aq. Na₂S₂O₃ (3×30 mL). The resulting organic layer was washed with 1 M disodium EDTA (2×20 mL), dried over MgSO₄, filtered and concentrated under reduced pressure. This residue was purified by column chromatography using a RediSep cartridge (120 g, silica gel) eluting with a 2.5-15% MeOH in DCM gradient. The desired fractions were concentrated under reduced pressure to provide the title compound as a white solid.

Step 3: Preparation of (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)-1-((R)-2-amino-3-cyclohexylpropanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide Hydrochloride

To a solution of compound 43 (2.37 g, 3.57 mmol) in MeOH (7 mL) was added 4 M HCl in dioxane (7.1 mL, 28.5 mmol) and the reaction mixture was stirred at 23° C. After 2 hours, the mixture was concentrated under reduced pressure. The resulting solid was dissolved in THF and concentrated under reduced pressure to provide the title compound.

Intermediate M: (2S,4S)—N-(4-(2-amino-2-oxoacetyl)-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1-((R)-2-amino-3-cyclohexylpropanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide Hydrochloride

Step 1: Preparation of tert-butyl ((2R)-1-((2S,4S)-2-((4-(2-amino-1-hydroxy-2-oxoethyl)-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)carbamoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidin-1-yl)-3-cyclohexyl-1-oxopropan-2-yl)carbamate (44)

To a solution of compound 42 (9.5 g, 14.3 mmol) in DCM (250 mL) was added mCPBA (70 wt %, 8.8 g, 35.7 mmol) and the reaction mixture was stirred at 23° C. After 1 hour, the mixture was partitioned between 10% aq. Na₂S₂O₃ (10 mL), sat. aq. NaHCO₃ (100 mL) and DCM (300 mL). The aqueous layer was extracted with DCM (400 mL). The combined extracts were washed with water (100 mL), dried over MgSO₄, filtered and concentrated under reduced pressure. This residue was purified by column chromatography using a RediSep cartridge (330 g, silica gel) eluting with a 0-15% MeOH in DCM gradient. The desired fractions were concentrated under reduced pressure to provide the title compound.

Step 2: Preparation of tert-butyl ((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)carbamoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidin-1-yl)-3-cyclohexyl-1-oxopropan-2-yl)carbamate (45)

To a solution of compound 44 (6.97 g, 10 mmol) in DCM (200 mL) was added NaHCO₃ (882 mg, 10.5 mmol) and DMP (4.45 g, 10.5 mmol) and the reaction mixture was stirred at 23° C. After 2 hours, the mixture was quenched with 10% aq. Na₂S₂O₃ (5 mL), diluted with water (75 mL) and extracted with DCM (2×300 mL). The combined extracts were washed with sat. aq. NaHCO₃ (75 mL), dried over MgSO₄, filtered and concentrated under reduced pressure. This residue was purified by column chromatography using a RediSep cartridge (330 g, silica gel) eluting with a 0-15% MeOH in DCM gradient. The desired fractions were concentrated under reduced pressure to provide the title compound.

Step 3: Preparation of (2S,4S)—N-(4-(2-amino-2-oxoacetyl)-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1-((R)-2-amino-3-cyclohexylpropanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide Hydrochloride

The title compound was prepared in a similar manner to Intermediate L using compound 45.

PREPARATION OF EXAMPLES Example 1: tert-butyl 4-((2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamido)-4-(2-amino-2-oxoacetyl)piperidine-1-carboxylate

Step 1: Preparation of Benzyl 4-((2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamido)-4-(2-amino-1-hydroxy-2-oxoethyl)piperidine-1-carboxylate (46)

The title compound was prepared in a similar manner to Intermediate J, step 1, using Intermediate I and Intermediate A.

Step 2: Preparation of (2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-(4-(2-amino-1-hydroxy-2-oxoethyl)piperidin-4-yl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide Hydrochloride (47)

To a degassed solution of compound 46 (222 mg, 0.265 mmol) and 1 M aq. HCl (260 μL, 0.260 mmol) in MeOH (10 mL) was added Pd(OH)₂ (44 mg, 0.03 mmol) and the mixture was stirred under a balloon of H₂ for 4 hours. The suspension was filtered through celite and the filtrate was concentrated under reduced pressure to provide the title compound.

Step 3: Preparation of tert-butyl 4-((2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamido)-4-(2-amino-1-hydroxy-2-oxoethyl)piperidine-1-carboxylate (48)

To a solution of compound 47 (128 mg, 0.173 mmol) in DMF (0.5 mL) was added Boc₂O and iPr₂EtN (60 μL, 0.346 mmol) and the reaction mixture was allowed to stand at 23° C. After 18 hours, water (3 mL) was added and the mixture was extracted with EtOAc (2×5 mL). The combined extracts were dried over MgSO₄, filtered and concentrated under reduced pressure. This residue was purified by column chromatography using a RediSep cartridge (4 g, silica gel) eluting with a 0-20% MeOH in DCM gradient. The desired fractions were concentrated under reduced pressure to provide the title compound.

Step 4: Preparation of tert-butyl 4-((2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamido)-4-(2-amino-2-oxoacetyl)piperidine-1-carboxylate

To a solution of compound 48 (93 mg, 0.116 mmol) in DCM (2 mL) was added DMP (64 mg, 0.15 mmol) and the reaction mixture was stirred at 23° C. After 1 hour, additional DMP (20 mg, 0.05 mmol) was added and the reaction mixture was stirred at 23° C. After 1 hour, 10% aq. Na₂S₂O₃ (2 mL) and water (2 mL) were added and the mixture was extracted with DCM (2×5 mL). The combined organic extracts were dried over MgSO₄, filtered and concentrated under reduced pressure. This residue was purified by column chromatography using a RediSep cartridge (4 g, silica gel) eluting with a 0-20% MeOH in DCM gradient. The desired fractions were concentrated under reduced pressure to provide the title compound as a white solid. MS (ESI+): 801 (M+1)^(⊕)

Example 2: (2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide

Step 1: Preparation of (2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-(4-(2-amino-1-hydroxy-2-oxoethyl)tetrahydro-2H-pyran-4-yl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide (49)

To a mixture of Intermediate I (868 mg, 1.58 mmol), Intermediate B (275 mg, 1.58 mmol) and HATU (661 mg, 1.74 mmol) in DMF (4 mL) was added iPr₂EtN (550 μL, 3.16 mmol) and the reaction mixture was stirred at 23° C. After 1 hour, this solution was partitioned between water (20 mL) and EtOAc (2×50 mL). The combined extracts were washed with 1 N aq. HCl (20 mL) and then sat. aq. NaHCO₃ (20 mL). This extract was dried over MgSO₄, filtered and concentrated under reduced pressure. This residue was purified by column chromatography using a RediSep cartridge (80 g, silica gel) eluting with a 0-15% MeOH in DCM gradient. The desired fractions were concentrated under reduced pressure to provide the title compound.

Step 2: Preparation of (2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide

To a solution of compound 49 (450 mg, 0.64 mmol) in DCM (6 mL) cooled to 0° C. in an ice bath was added DMP (271 mg, 0.64 mmol). The cooling bath was removed and the mixture was stirred at 23° C. for 2 hours. To this mixture was added 10% aq. Na₂S₂O₃ (10 mL) and DCM (10 mL) and the reaction mixture was stirred for 10 minutes. The resulting layers were separated with an Isolute phase separator and the aqueous was back extracted with DCM (10 mL) and separated. The combined extracts were concentrated under reduced pressure and the resulting residue was purified by column chromatography using a RediSep Gold cartridge (24 g, silica gel) eluting with a 0-10% MeOH in DCM gradient. The desired fractions were concentrated under reduced pressure to provide the title compound as a white solid. MS (ESI+): 702 (M+1)^(⊕); ¹H NMR (300 MHz, CD₃OD): δ 8.24-8.18 (1H, m), 8.00-7.83 (4H, m), 7.66-7.51 (3H, m), 5.93-5.82 (1H, m), 5.04-4.96 (1H, m), 4.78-4.60 (1H, m), 4.34-4.25 (2H, m), 3.90-3.64 (4H, m), 2.90-2.65 (2H, m), 2.20-1.94 (4H, m), 1.68 (3H, s), 1.63 (3H, s), 1.80-1.60 (6H, m), 1.52-0.91 (7H, m) ppm.

Example 3: (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-(methylsulfonyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide

To a mixture of 4-(methylsulfonyl)benzoic acid (Combi-Blocks, CA, catalog #OR-0048) (659 mg, 3.29 mmol), Intermediate J (1.6 g, 2.74 mmol) and HATU (1.46 g, 3.84 mmol) in DMF (6 mL) and DCM (16 mL) was added iPr₂EtN (52 μL, 0.3 mmol) and the reaction mixture was stirred at 23° C. for 18 hours. The mixture was partitioned between EtOAc (100 mL) and sat. aq. NaHCO₃ (100 mL) and the aqueous layer was extracted with EtOAc (3×100 mL). The combined extracts were washed with brine (100 mL), dried over MgSO₄, filtered and concentrated under reduced pressure. This residue was purified by column chromatography using a RediSep Gold cartridge (120 g, silica gel) eluting with a 0-12.5% MeOH in DCM gradient. The desired fractions were concentrated under reduced pressure to provide the title compound as a white solid. MS (ESI+): 730 (M+1)^(⊕)

Example 4: (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-(piperidin-1-ylsulfonyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide

To a mixture of 4-(piperidin-1-ylsulfonyl)benzoic acid (Enamine, NJ, catalog #EN300-00395) (554 mg, 2.06 mmol), Intermediate J (1.2 g, 2.06 mmol) and HATU (783 mg, 2.06 mmol) in DMF (8 mL) was added iPr₂EtN (360 μL, 2.06 mmol) and the reaction mixture was stirred at 23° C. for 18 hours. This mixture was partitioned between DCM (20 mL) and water (30 mL) and separated using an Isolute phase separator. The aqueous layer was extracted with DCM (2×20 mL). The organic extracts were combined and concentrated under reduced pressure. This residue was purified by column chromatography using a RediSep Gold cartridge (80 g+12 g precartridge, silica gel) eluting with a 0-10% MeOH in DCM gradient. The desired fractions were concentrated under reduced pressure to provide the title compound as a white solid. MS (EST+): 799 (M+1)^(⊕); ¹H NMR (300 MHz, CD₃OD): δ 8.04 (2H, d, J=8.2 Hz), 7.83 (2H, d, J=8.2 Hz), 7.55 (1H, s), 5.88 (1H, m), 4.99 (1H, m), 4.53 (1H, t, J=8.4 Hz), 4.34-4.29 (2H, m), 3.82-3.66 (4H, m), 2.99-2.96 (4H, m), 2.85 (1H, m), 2.73 (1H, m), 2.18-1.85 (4H, m), 1.78-1.71 (3H, m), 1.66 (3H, s), 1.64 (3H, s), 1.80-1.64 (6H, m), 1.44 (4H, m), 1.23-0.98 (6H, m) ppm.

The following compounds were prepared in a similar manner as Example 3 substituting 4-(methylsulfonyl)benzoic acid with a series of commercially available carboxylic acids. The reaction solvent was DMF or a DMF/DCM mixture. The mixtures were purified, as in Example 3, by column chromatography using a RediSep Gold silica gel cartridge eluting with a 0-12.5% MeOH in DCM gradient. Alternatively, the crude DMF mixtures were purified directly by reverse phase column chromatography using a C18 RediSep Gold cartridge eluting with a 0-60% ACN in water gradient containing 0.1% formic acid. The desired fractions were concentrated under reduced pressure to provide the title compounds as white solids.

Example Structure/Name MW MS (ESI+) Example 5

691.78 693 (M + 1)^(⊕) Example 6

676.76 677 (M + 1)^(⊕) Example 7

702.8  703 (M + 1)^(⊕) Example 8

691.78 692 (M + 1)^(⊕) Example 9

773.9  774 (M + 1)^(⊕) Example 10

765.82 766 (M + 1)^(⊕) Example 11

772.87 773 (M + 1)^(⊕) Example 12

731.84 732 (M + 1)^(⊕) Example 13

731.84 732 (M + 1)^(⊕) Example 14

767.82 768 (M + 1)^(⊕) Example 15

785.81 768 (M + 1)^(⊕) Example 16

817.78 818 (M + 1)^(⊕) Example 17

709.83 710 (M + 1)^(⊕) Example 18

765.78 766 (M + 1)^(⊕) Example 19

749.78 750 (M + 1)^(⊕) Example 20

692.76 693 (M + 1)^(⊕) Example 21

692.76 693 (M + 1)^(⊕) Example 22

708.83 709 (M + 1)^(⊕) Example 23

691.77 692 (M + 1)^(⊕) Example 24

690.79 691 (M + 1)^(⊕) Example 25

690.79 691 (M + 1)^(⊕) Example 26

669.74 670 (M + 1)^(⊕) Example 27

723.82 724 (M + 1)^(⊕) Example 28

757.9  759 (M + 1)^(⊕) Example 29

755.88 756 (M + 1)^(⊕) Example 30

691.78 692 (M + 1)^(⊕) Example 31

692.77 693 (M + 1)^(⊕) Example 32

691.78 692 (M + 1)^(⊕) Example 33

691.78 692 (M + 1)^(⊕) Example 34

747.83 748 (M + 1)^(⊕) Example 35

743.87 744 (M + 1)^(⊕) Example 36

783.93 784 (M + 1)^(⊕) Example 37

743.87 744 (M + 1)^(⊕) Example 38

783.81 784 (M + 1)^(⊕) Example 39

779.85 780 (M + 1)^(⊕) Example 40

758.88 759 (M + 1)^(⊕) Example 41

730.83 731 (M + 1)^(⊕) Example 42

770.9  771 (M + 1)^(⊕) Example 43

784.92 785 (M + 1)^(⊕) Example 44

786.94 809 (M + 1)^(⊕) Example 45

800.92 801 (M + 1)^(⊕) Example 46

765.82 766 (M + 1)^(⊕) Example 47

765.82 766 (M + 1)^(⊕) Example 48

769.91 770 (M + 1)^(⊕) Example 49

784.92 785 (M + 1)^(⊕) Example 50

812.86 813 (M + 1)^(⊕) Example 51

768.88 769 (M + 1)^(⊕) Example 52

784.92 785 (M + 1)^(⊕) Example 53

794.87 795 (M + 1)^(⊕)

Example 54: (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyclohexyl-2-(6-(oxetan-3-yloxy)-2-naphthamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide

Step 1: Preparation of methyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-naphthoate (50)

A mixture of methyl 6-bromo-2-naphthoate (1.00 g, 3.77 mmol), bis(pinacolato) diboron (1.15 g, 4.53 mmol), X-Phos G2 (60 mg, 0.07 mmol) and KOAc (1.11 g, 11.3 mmol) was degassed with nitrogen (repeat 3 times) and then dioxane (10 mL) was added and the reaction mixture was heated to 80° C. After 1 hour, the mixture was loaded directly onto a RediSep cartridge (80 g, silica gel) and eluted with a 0-30% EtOAc in hexane gradient. The desired fractions were concentrated under reduced pressure to provide the title compound as a beige solid.

Step 2: Preparation of methyl 6-(oxetan-3-yloxy)-2-naphthoate (51)

A mixture of compound 50 (100 mg, 0.32 mmol), copper(II)acetate hydrate (128 mg, 0.64 mmol) and Na₂CO₃ (135 mg, 1.28 mmol) was suspended in oxetan-3-ol (1 mL) and the reaction mixture was stirred at 105° C. After 30 minutes, the mixture was loaded directly onto a C18 pre-cartridge and purified through a reversed phase C18 RediSep cartridge (40 g) eluting with a 0-70% ACN in water gradient containing 0.1% formic acid. The desired fractions were concentrated under reduced pressure to provide the title compound.

Step 3: Preparation of Lithium 6-(oxetan-3-yloxy)-2-naphthoate (52)

To compound 51 (42 mg, 0.16 mmol) was added 0.33 M LiOH in THF/MeOH/H₂O (1:1:1) (0.96 mL, 0.32 mmol) and the solution was stirred at 23° C. After 2 hours, the mixture was concentrated under reduced pressure to provide the title compound.

Step 4: Preparation of (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyclohexyl-2-(6-(oxetan-3-yloxy)-2-naphthamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide

The title compound was prepared in a similar manner to Example 3 using compound 52. MS (ESI+): 774 (M+1)^(⊕)

Example 55: (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyclohexyl-2-(6-(oxetan-3-yl)-2-naphthamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide

Step 1: Preparation of (6-(methoxycarbonyl)naphthalen-2-yl)boronic Acid (53)

To compound 50 (300 mg, 0.96 mmol) and isobutyl boronic acid (490 mg, 4.81 mmol) in MeOH/THF (1:1, 10 mL) was added 1 M aq. HCl (3.84 mL, 3.84 mmol) and the reaction mixture was stirred at 23° C. After 18 hours, the resulting layers were partitioned and the hexanes layer was extracted further with MeOH (2×20 mL). The combined MeOH extracts were washed with hexanes (2×20 mL) and concentrated under reduced pressure to provide the title compound as a white solid.

Step 2: Preparation of Isopropyl 6-(oxetan-3-yl)-2-naphthoate (54)

To a mixture of compound 53 (147 mg, 0.64 mmol), NaHMDS (117 mg, 0.64 mmol), NiI₂ (5.9 mg, 0.019 mmol) and (1R,2R)-cyclohexane-1,2-diamine hydrochloride (2.9 mg, 0.019 mmol) in iPrOH (1.2 mL) flushed with nitrogen was added a solution of 3-iodooxetane (59 mg, 0.32 mmol) in iPrOH. This mixture was sealed, stirred and heated in a microwave reactor (Biotage) to 80° C. for 20 minutes. After this time, the resulting mixture was loaded directly on a pre-cartridge and purified by column chromatography using a RediSep Gold cartridge (24 g, silica gel) eluting with a 0-40% EtOAc in hexanes gradient. The desired fractions were concentrated under reduced pressure to provide the title compound as the isopropyl ester

Step 3: Preparation of Lithium 6-(oxetan-3-yl)-2-naphthoate (55)

The title compound was prepared in a similar manner to compound 52 using compound 54.

Step 4: Preparation of (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyclohexyl-2-(6-(oxetan-3-yl)-2-naphthamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide

The title compound was prepared in a similar manner to Example 3 using compound 55. MS (ESI+): 758 (M+1)^(⊕)

Example 56: (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-(N-(3,3-difluorocyclobutyl)sulfamoyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide

Step 1: Preparation of 4-(N-(3,3-difluorocyclobutyl)sulfamoyl)benzoic Acid (56)

To a solution of 4-(chlorosulfonyl)benzoic acid (250 mg, 1.13 mmol) in MeOH (5 mL) was added 3,3-difluorocyclobutan-1-amine hydrochloride (Enamine, NJ, catalog #EN300-78062) (197.0 mg, 1.356 mmol) and TEA (395 μL, 2.84 mmol) and the reaction mixture was stirred at 23° C. After 18 hours, the reaction mixture was quenched with 1 M aq. HCl (4.5 mL) and the resulting beige mixture was filtered to provide the title compound as a beige solid.

Step 2: Preparation of (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-(N-(3,3-difluorocyclobutyl)sulfamoyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide

The title compound was prepared in a similar manner to Example 3 using compound 56. MS (ESI+): 821 (M+1)^(⊕)

Example 57: (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyclohexyl-2-(3-phenylureido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide

To a suspension of Intermediate J (50 mg, 0.085 mmol) in DCM (1 mL) cooled to 0° C. in an ice bath was added phenyl isocyanate (10.5 μL, 0.095 mmol) and iPr₂EtN (44.5 μL, 0.255 mmol) and this solution was allowed to stand at 0° C. After 18 hours, this solution was loaded directly onto a RediSep cartridge (12 g, silica gel) and eluted with a 0-15% MeOH in DCM gradient. The desired fractions were concentrated under reduced pressure to provide the title compound. MS (ESI+): 668 (M+1)^(⊕)

The following compounds were prepared in a similar manner as Example 57 substituting phenyl isocyanate with a series of commercially available isocyanates.

Example Structure/Name MW MS (ESI+) Example 58

716.83 717   (M + 1)^(⊕) Example 59

734.77 735   (M + 1)^(⊕) Example 60

719.83 720   (M + 1)^(⊕) Example 61

719.2  719.5 (M + 1)^(⊕) Example 62

672.82 673   (M + 1)^(⊕) Example 63

716.83 717   (M + 1)^(⊕) Example 64

750.88 751   (M + 1)^(⊕) Example 65

680.79 681   (M + 1)^(⊕) Example 66

691.78 692   (M + 1)^(⊕) Example 67

744.86 745   (M + 1)^(⊕)

Example 68: (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyclohexyl-2-(naphthalene-2-sulfonamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide

To a suspension of Intermediate J (50 mg, 0.085 mmol) and iPr₂EtN (44.5 μL, 0.255 mmol) in DCM (1 mL) cooled to 0° C. in an ice bath was added naphthalene-2-sulfonyl chloride (21.5 mg, 0.095 mmol) and this solution was allowed to stand at 0° C. After 18 hours, this solution was loaded directly onto a RediSep cartridge (12 g, silica gel) and eluted with a 0-15% MeOH in DCM gradient. The desired fractions were concentrated under reduced pressure to provide the title compound. MS (ESI+): 738 (M+1)^(⊕)

The following compounds were prepared in a similar manner as Example 68 substituting naphthalene-2-sulfonyl chloride with a series of commercially available sulfonyl chlorides.

Example Structure/Name MW MS (ESI+) Example 69

723.79 724 (M + 1)^(⊕) Example 70

753.81 754 (M + 1)^(⊕)

Example 71: (2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-(3-(2-amino-2-oxoacetyl)tetrahydrofuran-3-yl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide

Step 1: Preparation of (2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-(3-(2-amino-1-hydroxy-2-oxoethyl)tetrahydrofuran-3-yl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide (57)

To a solution of Intermediate I (152 mg, 0.276 mmol), Intermediate C (106 mg, 0.662 mmol) and HATU (124 mg, 0.331 mmol) in DMF (2.7 mL) was added iPr₂EtN (193 μL, 1.104 mmol) and the reaction mixture was stirred at 23° C. After 1 hour, residual Intermediate I was consumed by reacting with additional HATU (60 mg, 0.158 mmol) and benzylamine (22 μL, 0.2 mmol). The reaction mixture was loaded directly onto a C18 pre-cartridge and purified by column chromatography using reverse phase C18 RediSep Gold cartridge (80 g) eluting with a 0-100% ACN in water gradient containing 0.1% formic acid. The desired fractions were concentrated under reduced pressure to provide the title compound.

Step 2: Preparation of (2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-(3-(2-amino-2-oxoacetyl)tetrahydrofuran-3-yl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide

To a solution of compound 57 (50 mg, 0.073 mmol) in DMSO (1 mL) was added IBX (45 wt %, 90 mg, 0.145 mmol) and the reaction mixture was stirred at 23° C. After 18 hours, additional IBX (90 mg, 0.145 mmol) was added and the mixture was stirred for 6 hours. The mixture was then quenched with 10% aq. Na₂S₂O₃ (1 mL) and loaded directly onto a C18 pre-cartridge and purified by column chromatography using reverse phase C18 RediSep cartridge (15.5 g) eluting with a 0-70% ACN in water gradient containing 0.1% formic acid. The desired fractions were concentrated under reduced pressure to provide the title compound as a white solid. MS (ESI+): 688 (M+1)^(⊕)

Example 72: (2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-(4-(2-amino-2-oxoacetyl)oxepan-4-yl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide

The title compound was prepared in a similar manner to Example 71 using Intermediate D. MS (ESI+): 716 (M+1)^(⊕)

Examples 73 and 74: Diastereomers of (2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-(4-(2-amino-2-oxoacetyl)oxepan-4-yl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide (Example 72)

The diasteomeric mixture of Example 72 (180 mg, 0.25 mmol) was separated using a Semi-Prep SFC ChiralPak ID column (10×250 mm, 5 μm) with an isocratic 40% MeOH+10 mM ammonium formate at 10 mL/min, 100 Bar, 35° C. to provide (2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N—((R or S)-4-(2-amino-2-oxoacetyl)oxepan-4-yl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide, Example 73 (second eluting peak) and (2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N—((S or R)-4-(2-amino-2-oxoacetyl)oxepan-4-yl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide, Example 74 (first eluting peak). MS (EST+): 716 (M+1)

716 (M+1)

Example 75: (2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide

Step 1: Preparation of (2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-(4-(2-amino-1-hydroxy-2-oxoethyl)tetrahydro-2H-thiopyran-4-yl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide (59)

To a mixture of Intermediate I (222 mg, 0.405 mmol), Intermediate E (92.5 mg, 0.486 mmol) and HATU (154 mg, 0.405 mmol) in DMF (2 mL) was added iPr₂EtN (211 μL, 1.21 mmol) and the reaction mixture was stirred at 23° C. After 1 hour, water (10 mL) was added and the mixture extracted with EtOAc (2×20 mL). The combined extracts were washed with 1 M aq. HCl (10 mL) and then sat. aq. NaHCO₃ (10 mL). This extract was dried over MgSO₄, filtered and concentrated under reduced pressure. This residue was purified by column chromatography using a RediSep cartridge (12 g, silica gel) eluting with a 0-10% MeOH in DCM gradient. The desired fractions concentrated under reduced pressure to provide the title compound.

Step 2: Preparation of (2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide

To a solution of compound 59 (146 mg, 0.20 mmol) in DCM (8 mL) was added 10% palladium on carbon (475 mg, 0.44 mmol) and the reaction mixture was stirred at 23° C. After 30 minutes, DMP (189 mg, 0.44 mmol) was added and the mixture was stirred at 23° C. After 2 hours, the mixture was quenched with 10% aq. Na₂S₂O₃ (1 mL), diluted with sat. aq. NaHCO₃ (2 mL) and then filtered through a plug of celite. The celite plug was rinsed further with DCM (10 mL) and MeOH (5 mL). The combined filtrates were partitioned using an Isolute phase separator and the combined organic extract was concentrated under reduced pressure. This residue was purified by column chromatography using a reverse phase C18 RediSep Gold cartridge (12 g) eluting with a 20-100% ACN in water gradient containing 0.1% formic acid. The desired fractions were concentrated under reduced pressure to provide the title compound. MS (ESI+): 718 (M+1)^(⊕)

Example 76: (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-((difluoromethyl)sulfonyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide

To a mixture of 4-((difluoromethyl)sulfonyl)benzoic acid (Enamine, NJ, catalog #EN300-09067) (512 mg, 2.17 mmol), Intermediate L (1.3 g, 2.17 mmol) and HATU (824 mg, 2.17 mmol) in DMF (10 mL) was added iPr₂EtN (1.13 mL, 6.5 mmol) and the reaction mixture was stirred at 23° C. for 1 hour. The mixture was partitioned between EtOAc (100 mL) and water (50 mL) and the aqueous layer extracted with EtOAc (100 mL). The combined extracts were dried over MgSO₄, filtered and concentrated under reduced pressure. This residue was purified by column chromatography using a RediSep Gold cartridge (120 g, silica gel) eluting with a 0-10% MeOH in DCM gradient. The desired fractions were concentrated under reduced pressure to provide the title compound as a white solid. MS (ESI+): 782 (M+1)^(⊕); ¹H NMR (300 MHz, CD₃OD): δ 8.18 (2H, d, J=7.8 Hz), 8.06 (2H, d, J=7.8 Hz), 7.54 (1H, s), 6.77 (1H, t, J_(H-F)=53 Hz), 5.94-5.80 (1H, m), 5.06-4.95 (1H, m), 4.56 (1H, t, J=8 Hz), 4.43-4.25 (2H, m), 3.10-2.64 (4H, m), 2.57-2.34 (4H, m), 2.06 (2H, t, J=12 Hz), 1.91 (1H, d, J=12 Hz), 1.74 (5H, br s), 1.66 (6H, s), 1.52-0.90 (7H, m) ppm.

The following compounds were prepared in a similar manner as Example 76 substituting 4-((difluoromethyl)sulfonyl)benzoic acid with a series of commercially available carboxylic acids. The reaction mixtures were purified, as in Example 76, by column chromatography using a RediSep Gold silica gel cartridge eluting with a 0-10% MeOH in DCM gradient. Alternately, the crude DMF mixtures were purified directly by reverse phase column chromatography using a C18 RediSep Gold cartridge eluting with a 0-60% ACN in water gradient containing 0.1% formic acid. The desired fractions were concentrated under reduced pressure to provide the title compounds as white solids.

Example Structure/Name MW MS (ESI+) Example 77

745.91 746 (M + 1)^(⊕) Example 78

668.81 669 (M + 1)^(⊕) Example 79

759.94 760 (M + 1)^(⊕) Example 80

707.84 708 (M + 1)^(⊕) Example 81

734.86 735 (M + 1)^(⊕) Example 82

771.95 772 (M + 1)^(⊕) Example 83

786.96 787 (M + 1)^(⊕) Example 84

722.86 723 (M + 1)^(⊕) Example 85

722.86 723 (M + 1)^(⊕) Example 86

722.86 723 (M + 1)^(⊕) Example 87

789.96 790 (M + 1)^(⊕) Example 88

708.83 709 (M + 1)^(⊕) Example 89

710.84 711 (M + 1)^(⊕) Example 90

667.82 669 (M + 1)^(⊕) Example 91

668.81 669 (M + 1)^(⊕) Example 92

784.95 785 (M + 1)^(⊕) Example 93

836.97 837 (M + 1)^(⊕) Example 94

802.96 803 (M + 1)^(⊕) Example 95

816.99 817 (M + 1)^(⊕) Example 96

760.92 761 (M + 1)^(⊕) Example 97

774.95 775 (M + 1)^(⊕) Example 98

774.95 775 (M + 1)^(⊕) Example 99

773.96 774 (M + 1)^(⊕) Example 100

785.97 786 (M + 1)^(⊕) Example 101

810.93 811 (M + 1)^(⊕) Example 102

858.04 859 (M + 1)^(⊕) Example 103

764.93 765 (M + 1)^(⊕) Example 104

785.97 786 (M + 1)^(⊕) Example 105

738.9  739 (M + 1)^(⊕) Example 106

800.99 802 (M + 1)^(⊕) Example 107

830.03 831 (M + 1)^(⊕) Example 108

786.96 788 (M + 1)^(⊕) Example 109

800.99 802 (M + 1)^(⊕) Example 110

800.99 802 (M + 1)^(⊕) Example 111

800.99 802 (M + 1)^(⊕) Example 112

828.92 830 (M + 1)^(⊕) Example 113

847.08 848 (M + 1)^(⊕)

Example 114: (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-((3,3-difluoroazetidin-1-yl)sulfonyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide

Preparation of (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-((3,3-difluoroazetidin-1-yl)sulfonyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide

The title compound was prepared in a similar manner to Example 76 using 4-((3,3-difluoroazetidin-1-yl)sulfonyl)benzoic acid, which was prepared in a similar manner as Example 56, step 1, using 3,3-difluoroazetidine hydrochloride. MS (ESI+): 823 (M+1)^(⊕)

The following compounds were prepared in a similar manner as Example 114 and Example 56, step 1, substituting 3,3-difluoroazetidine hydrochloride with other commercially available amines. The reaction mixtures were purified by column chromatography using a RediSep Gold silica gel cartridge eluting with a 0-12.5% MeOH in DCM gradient. Alternatively, the crude DMF mixtures were purified directly by reverse phase column chromatography using a C18 RediSep Gold cartridge eluting with a 0-60% ACN in water gradient containing 0.1% formic acid. The desired fractions were concentrated under reduced pressure to provide the title compounds as white solids.

Example Structure/Name MW MS (ESI+) Example 115

829.00 830 (M + 1)^(⊕) (2S,4S)-1-((R)-2-(4-(2-oxa-6-azaspiro[3.3]heptan-6- ylsulfonyl)benzamido)-3-cyclohexylpropanoyl)-N-(4-(2- amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)-4-(5- (2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1- yl)pyrrolidine-2-carboxamide Example 116

845.04 846 (M + 1)^(⊕) (2S,4S)-N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H- thiopyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-(N-(3,3- dimethyl-2-oxobutyl)sulfamoyl)benzamido)propanoyl)- 4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1 yl)pyrrolidine-2-carboxamide

Example 117: (2S,4S)—N-(4-(2-amino-2-oxoacetyl)-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-(pyrrolidin-1-ylsulfonyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide

To a mixture of Intermediate M (189.3 mg, 0.3 mmol), 4-(pyrrolidin-1-ylsulfonyl)benzoic acid (77 mg, 0.31 mmol) and HATU (141 mg, 0.37 mmol) in DMF (2 mL) was added iPr₂EtN (216 μL, 1.24 mmol) and the reaction mixture was stirred at 23° C. After 1 hour, the mixture was directly purified by reverse phase chromatography using a C18 RediSep Gold cartridge (50 g) and eluting with a 0-60% ACN in water gradient containing 0.1% formic acid. The desired fractions were concentrated under reduced pressure to provide the title compound. MS (ESI+): 833 (M+1)^(⊕); ¹H NMR (300 MHz, CD₃OD) δ 8.05 (2H, d, J=7.1 Hz), 7.90 (2H, d, J=8.0 Hz), 7.55 (1H, s), 5.90-5.88 (1H, m), 4.86-4.81 (1H, m), 4.57-4.55 (1H, m), 4.31-4.29 (2H, m), 3.50-3.41 (4H, m), 3.06-2.93 (2H, m), 2.90-2.65 (4H, m), 2.63-2.42 (2H, m), 2.00-1.85 (1H, m), 1.85 (9H, br s), 1.68-1.57 (9H, m), 1.54-1.35 (1H, m), 1.35-1.14 (3H, m), 1.13-0.84 (2H, m) ppm.

The following compounds were prepared in a similar manner as Example 117 substituting 4-(pyrrolidin-1-ylsulfonyl)benzoic acid with other commercially available carboxylic acids. Purification may alternatively be accomplished using normal phase chromatography using a RediSep Gold silica gel cartridge eluting with a 0-12.5% MeOH in DCM gradient.

Example Structure/Name MW MS (ESI+) Example 118

749.88 750 (M + 1)^(⊕) (2S,4S)-1-((R)-2-(2-naphthamido)-3- cyclohexylpropanoyl)-N-(4-(2-amino-2-oxoacetyl)-1,1- dioxidotetrahydro-2H-thiopyran-4-yl)-4-(5-(2- hydroxypropan-2-yl)-1H-1,2,3-triazol-1- yl)pyrrolidine-2-carboxamide Example 119

777.91 778 (M + 1)^(⊕) (2S,4S)-N-(4-(2-amino-2-oxoacetyl)-1,1- dioxidotetrahydro-2H-thiopyran-4-yl)-1-((R)-3- cyclohexyl-2-(4- (methylsulfonyl)benzamido)propanoyl)-4-(5-(2- hydroxypropan-2-yl)-1H-1,2,3-triazol-1- yl)pyrrolidine-2-carboxamide Example 120

813.89 814 (M + 1)^(⊕) (2S,4S)-N-(4-(2-amino-2-oxoacetyl)-1,1- dioxidotetrahydro-2H-thiopyran-4-yl)-1-((R)-3- cyclohexyl-2-(4- ((difluoromethyl)sulfonyl)benzamido)propanoyl)-4-(5- (2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1- yl)pyrrolidine-2-carboxamide Example 121

750.86 751 (M + 1)^(⊕) N-((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)-1,1- dioxidotetrahydro-2H-thiopyran-4-yl)carbamoyl)-4-(5- (2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1- yl)pyrrolidin-1-yl)-3-cyclohexyl-1-oxopropan-2- yl)quinoline-3-carboxamide Example 122

739.84 740 (M + 1)^(⊕) N-((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)-1,1- dioxidotetrahydro-2H-thiopyran-4-yl)carbamoyl)-4-(5- (2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1- yl)pyrrolidin-1-yl)-3-cyclohexyl-1-oxopropan-2-yl)- 1H-indazole-7-carboxamide Example 123

724.83 726 (M + 1)^(⊕) (2S,4S)-N-(4-(2-amino-2-oxoacetyl)-1,1- dioxidotetrahydro-2H-thiopyran-4-yl)-1-((R)-2-(4- cyanobenzamido)-3-cyclohexylpropanoyl)-4-(5-(2- hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine- 2-carboxamide Example 124

739.84 740 (M + 1)^(⊕) N-((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)-1,1- dioxidotetrahydro-2H-thiopyran-4-yl)carbamoyl)-4-(5- (2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1- yl)pyrrolidin-1-yl)-3-cyclohexyl-1-oxopropan-2-yl)- 1H-indazole-6-carboxamide Example 125

742.84 743 (M + 1)^(⊕) N¹-((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)-1,1- dioxidotetrahydro-2H-thiopyran-4-yl)carbamoyl)-4-(5- (2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1- yl)pyrrolidin-1-yl)-3-cyclohexyl-1-oxopropan-2- yl)terephthalamide Example 126

744.82 745 (M + 1)^(⊕) (2S,4S)-N-(4-(2-amino-2-oxoacetyl)-1,1- dioxidotetrahydro-2H-thiopyran-4-yl)-1-((R)-3- cyclohexyl-2-(4-nitrobenzamido)propanoyl)-4-(5-(2- hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine- 2-carboxamide Example 127

778.71 780 (M + 1)^(⊕) (2S,4S)-N-(4-(2-amino-2-oxoacetyl)-1,1- dioxidotetrahydro-2H-thiopyran-4-yl)-1-((R)-2-(4- bromobenzamido)-3-cyclohexylpropanoyl)-4-(5-(2- hydroxypropan-2-yl)-1H-1,2,3-triazol-1- yl)pyrrolidine-2-carboxamide Example 128

770.24 770, 772 (M + 1)^(⊕) (2S,4S)-N-(4-(2-amino-2-oxoacetyl)-1,1- dioxidotetrahydro-2H-thiopyran-4-yl)-1-((R)-2-(4- chloro-2,5-difluorobenzamido)-3-cyclohexylpropanoyl)- 4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1- yl)pyrrolidine-2-carboxamide Example 129

768.71 768, 770 (M + 1)^(⊕) (2S,4S)-N-(4-(2-amino-2-oxoacetyl)-1,1- dioxidotetrahydro-2H-thiopyran-4-yl)-1-((R)-3- cyclohexyl-2-(3,4-dichlorobenzamido)propanoyl)-4-(5- (2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1- yl)pyrrolidine-2-carboxamide Example 130

716.8 717 (M + 1)^(⊕) N-((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)-1,1- dioxidotetrahydro-2H-thiopyran-4-yl)carbamoyl)-4-(5- (2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1- yl)pyrrolidin-1-yl)-3-cyclohexyl-1-oxopropan-2-yl)- 6-hydroxynicotinamide Example 131

766.86 767 (M + 1)^(⊕) N-((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)-1,1- dioxidotetrahydro-2H-thiopyran-4-yl)carbamoyl)-4-(5- (2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1- yl)pyrrolidin-1-yl)-3-cyclohexyl-1-oxopropan-2-yl)-1- hydroxyisoquinoline-3-carboxamide Example 132

768.85 769 (M + 1)^(⊕) N-((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)-1,1- dioxidotetrahydro-2H-thiopyran-4-yl)carbamoyl)-4-(5- (2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1- yl)pyrrolidin-1-yl)-3-cyclohexyl-1-oxopropan-2-yl)-7- fluoroquinoline-3-carboxamide Example 133

785.31 786 (M + 1)^(⊕) N-((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)-1,1- dioxidotetrahydro-2H-thiopyran-4-yl)carbamoyl)-4-(5- (2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1- yl)pyrrolidin-1-yl)-3-cyclohexyl-1-oxopropan-2-yl)- 7-chloroquinoline-3-carboxamide Example 134

818.96 819 (M + 1)^(⊕) (2S,4S)-N-(4-(2-amino-2-oxoacetyl)-1,1- dioxidotetrahydro-2H-thiopyran-4-yl)-1-((R)-3- cyclohexyl-2-(4-(N- cyclopropylsulfamoyl)benzamido)propanoyl)-4-(5-(2- hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine- 2-carboxamide Example 135

832.99 833 (M + 1)^(⊕) (2S,4S)-N-(4-(2-amino-2-oxoacetyl)-1,1- dioxidotetrahydro-2H-thiopyran-4-yl)-1-((R)-2-(4-(N- cyclobutylsulfamoyl)benzamido)-3- cyclohexylpropanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H- 1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide Example 136

873.05 874 (M + 1)^(⊕) (2S,4S)-N-(4-(2-amino-2-oxoacetyl)-1,1- dioxidotetrahydro-2H-thiopyran-4-yl)-1-((R)-3- cyclohexyl-2-(4-(N-(spiro[3.3]heptan-2- yl)sulfamoyl)benzamido)propanoyl)-4-(5-(2- hydroxypropan-2-yl)-1H-1,2,3-triazol-1- yl)pyrrolidine-2-carboxamide Example 137

842.93 843 (M + 1)^(⊕) (2S,4S)-N-(4-(2-amino-2-oxoacetyl)-1,1- dioxidotetrahydro-2H-thiopyran-4-yl)-1-((R)-3- cyclohexyl-2-(4-(N-(2,2- difluoroethyl)sulfamoyl)benzamido)propanoyl)-4-(5-(2- hydroxypropan-2-yl)-1H-1,2,3-triazol-1- yl)pyrrolidine-2-carboxamide Example 138

847.01 848 (M + 1)^(⊕) (2S,4S)-N-(4-(2-amino-2-oxoacetyl)-1,1- dioxidotetrahydro-2H-thiopyran-4-yl)-1-((R)-3- cyclohexyl-2-(4-(piperidin-1- ylsulfonyl)benzamido)propanoyl)-4-(5-(2- hydroxypropan-2-yl)-1H-1,2,3-triazol-1- yl)pyrrolidine-2-carboxamide Example 139

835 836 (M + 1)^(⊕) (2S,4S)-N-(4-(2-amino-2-oxoacetyl)-1,1- dioxidotetrahydro-2H-thiopyran-4-yl)-1-((R)-2-(4-(N- (tert-butyl)sulfamoyl)benzamido)-3- cyclohexylpropanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H- 1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide Example 140

854.99 855 (M + 1)^(⊕) (2S,4S)-N-(4-(2-amino-2-oxoacetyl)-1,1- dioxidotetrahydro-2H-thiopyran-4-yl)-1-((R)-3- cyclohexyl-2-(4-(N- phenylsulfamoyl)benzamido)propanoyl)-4-(5-(2- hydroxypropan-2-yl)-1H-1,2,3-triazol-1- yl)pyrrolidine-2-carboxamide Example 141

832.99 833 (M + 1)^(⊕) (2S,4S)-N-(4-(2-amino-2-oxoacetyl)-1,1- dioxidotetrahydro-2H-thiopyran-4-yl)-1-((R)-3- cyclohexyl-2-(4-(N-cyclopropyl-N- methylsulfamoyl)benzamido)propanoyl)-4-(5-(2- hydroxypropan-2-yl)-1H-1,2,3-triazol-1- yl)pyrrolidine-2-carboxamide Example 142

847.01 847.9 (M + 1)^(⊕) (2S,4S)-N-(4-(2-amino-2-oxoacetyl)-1,1- dioxidotetrahydro-2H-thiopyran-4-yl)-1-((R)-3- cyclohexyl-2-(4-(N-cyclopropyl-N- ethylsulfamoyl)benzamido)propanoyl)-4-(5-(2- hydroxypropan-2-yl)-1H-1,2,3-triazol-1- yl)pyrrolidine-2-carboxamide Example 143

847.01 847.9 (M + 1)^(⊕) (2S,4R)-N-(4-(2-amino-2-oxoacetyl)-1,1- dioxidotetrahydro-2H-thiopyran-4-yl)-1-((R)-3- cyclohexyl-2-(4-(N- cyclopentylsulfamoyl)benzamido)propanoyl)-4-(5-(2- hydroxypropan-2-yl)-1H-1,2,3-triazol-1- yl)pyrrolidine-2-carboxamide

Example 144: (2S,4S)—N-(4-(2-amino-2-oxoacetyl)-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-(N,N-dicyclopropylsulfamoyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide

Step 1: Preparation of 4-((3,3-difluoroazetidin-1-yl)sulfonyl)benzoic Acid (60)

The title compound was prepared in a similar manner as in compound 56 using dicyclopropylamine hydrochloride (Enamine, NJ, catalog #EN300-154277).

Step 2: Preparation of (2S,4S)—N-(4-(2-amino-2-oxoacetyl)-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-(N,N-dicyclopropylsulfamoyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide

The title compound was prepared in a similar manner to Example 117 using 4-((3,3-difluoroazetidin-1-yl)sulfonyl)benzoic acid and Intermediate M. MS (ESI+): 860 (M+1)^(⊕)

Example 145: (2S,4S)—N-(4-(2-amino-2-oxoacetyl)-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1-((R)-3-cyclohexyl-2-(naphthalene-2-sulfonamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide

The title compound was prepared in a similar manner as Example 68 using Intermediate M. MS (ESI+): 786 (M+1)^(⊕)

Example 146: (2S,4S)—N-(4-(2-amino-2-oxoacetyl)-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1-((R)-3-cyclohexyl-2-(3-(naphthalen-2-yl)ureido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide

The title compound was prepared in a similar manner as Example 57 using Intermediate M. MS (ESI+): 765 (M+1)^(⊕)

Example 147: (2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-(4-(2-amino-2-oxoacetyl)-1-oxidotetrahydro-2H-thiopyran-4-yl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide

To a solution of compound 59 (82 mg, 0.11 mmol) in DCM (4.4 mL) at 23° C. was added DMP (106 mg, 0.25 mmol) and the reaction mixture was stirred at 23° C. for 18 hours. After this time, the reaction was quenched with 10% aq. Na₂S₂O₃ (500 μL) and the resulting mixture was loaded directly onto a C18 pre-cartridge and purified using a C18 RediSep Gold cartridge (24 g) eluting with a 10-60% ACN in water gradient containing 0.1% formic acid. The desired fractions were concentrated under reduced pressure to provide the title compound as a white solid. MS (ESI+): 735 (M+1)^(⊕)

Example 148: (2S,4S)—N-(4-(2-amino-2-oxoacetyl)-1-oxidotetrahydro-2H-thiopyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-((difluoromethyl)sulfonyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide

To a solution of Example 76 (100 mg, 0.128 mmol) in DCM (5 mL) was added mCPBA (70 wt %, 21.5 mg, 0.096 mmol) and the reaction mixture was stirred at 23° C. for 30 minutes. After this time, the reaction was partitioned with sat. aq. NaHCO₃ (5 mL) and the organic extract was dried over MgSO₄, filtered and concentrated under reduced pressure. This residue was purified by reverse phase chromatography using a C18 RediSep Gold cartridge (30 g) eluting with a 10-60% ACN in water gradient containing 0.1% formic acid. The desired fractions were concentrated under reduced pressure to provide the title compound as a white solid. MS (ESI+): 798 (M+1)^(⊕)

Example 149: (2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-(3-(2-amino-2-oxoacetyl)tetrahydrothiophen-3-yl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide

The title compound was prepared in a similar manner as Example 75 using Intermediate F. MS (ESI+): 704 (M+1)^(⊕)

Example 150: (2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-(3-(2-amino-2-oxoacetyl)-1-oxidotetrahydrothiophen-3-yl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide

The title compound was prepared in a similar manner as Example 147 using compound 61. MS (ESI+): 720 (M+1)^(⊕)

Example 151: (2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-(3-(2-amino-2-oxoacetyl)-1,1-dioxidotetrahydrothiophen-3-yl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide

Step 1: Preparation of (2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-(3-(2-amino-1-hydroxy-2-oxoethyl)-1,1-dioxidotetrahydrothiophen-3-yl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide (62)

To a solution of compound 61 (50 mg, 0.07 mmol) in DCM (0.5 mL) was added mCPBA (77 wt %, 39 mg, 0.17 mmol) and the reaction mixture was stirred at 23° C. After 1 hour, the mixture was quenched with 10% aq. Na₂S₂O₃ (1 mL) and extracted with DCM (2 mL). The organic extracts were concentrated under reduced pressure. The residue was purified by column chromatography using a RediSep cartridge (4 g, silica gel) eluting with a 0-12% MeOH in DCM gradient. The desired fractions were concentrated under reduced pressure to provide the title compound.

Step 2: Preparation of (2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-(3-(2-amino-2-oxoacetyl)-1,1-dioxidotetrahydrothiophen-3-yl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide

The title compound was prepared in a similar manner as step 2 of Example 2 using compound 62, with stirring at 0° C. for 18 h to obtain the title compound as a white solid. MS (ESI+): 736 (M+1)^(⊕)

Example 152: (2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-(3-(2-amino-2-oxoacetyl)-1,1-dioxidotetrahydro-2H-thiopyran-3-yl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide

Step 1: Preparation of (2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-(3-(2-amino-1-hydroxy-2-oxoethyl)tetrahydro-2H-thiopyran-3-yl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide (63)

The title compound was prepared in a similar manner to Example 75 using Intermediate G.

Steps 2 and 3: Preparation of (2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-(3-(2-amino-2-oxoacetyl)-1,1-dioxidotetrahydro-2H-thiopyran-3-yl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide

The title compound was prepared in a similar manner to Example 151 using compound 63. MS (ESI+): 750 (M+1)^(⊕)

Example 153: (2S,4S)—N—((R or S)-4-(2-amino-2-oxoacetyl)oxepan-4-yl)-1-((R)-3-cyclohexyl-2-(4-((difluoromethyl)sulfonyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide

Step 1: Preparation of tert-butyl ((2R)-1-((2S,4S)-2-((4-(2-amino-1-hydroxy-2-oxoethyl)oxepan-4-yl)carbamoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidin-1-yl)-3-cyclohexyl-1-oxopropan-2-yl)carbamate (65)

The title compound was prepared in a similar manner to compound 38 using Intermediate D and DMF as solvent for 1 hour to provide the title compound.

Step 2: Preparation of tert-butyl ((2R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)oxepan-4-yl)carbamoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidin-1-yl)-3-cyclohexyl-1-oxopropan-2-yl)carbamate (66)

To a solution of compound 65 (1.72 g, 2.59 mmol) in DMSO (10 mL) was added IBX (45 wt %, 4.84 g, 7.77 mmol) and the reaction mixture was stirred at 23° C. After 18 hours, the reaction was cooled to 0° C. in an ice bath and then quenched with 10% aq. Na₂S₂O₃ (20 mL) and extracted with EtOAc (2×50 mL). The combined extracts were washed with sat. aq. NaHCO₃ (50 mL) and brine (50 mL) and then dried over MgSO₄, filtered and concentrated under reduced pressure. This residue was purified by column chromatography using a RediSep Gold cartridge (120 g, silica gel) eluting with a 0-25% MeOH in DCM gradient. The desired fractions were concentrated under reduced pressure to provide the title compound as a white solid.

Step 3: Separation of Diastereomers to Provide tert-butyl ((R)-1-((2S,4S)-2-(((R or S)-4-(2-amino-2-oxoacetyl)oxepan-4-yl)carbamoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidin-1-yl)-3-cyclohexyl-1-oxopropan-2-yl)carbamate, Compound 67 (First Eluting Peak) and tert-butyl ((R)-1-((2S,4S)-2-(((R or S)-4-(2-amino-2-oxoacetyl)oxepan-4-yl)carbamoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidin-1-yl)-3-cyclohexyl-1-oxopropan-2-yl)carbamate, Compounds, Compound 68 (Second Eluting Peak)

The mixture of diastereomers was separated in a similar manner to Example 73 and Example 74 to provide the title compounds.

Step 4: Preparation of (2S,4S)—N—((R or S)-4-(2-amino-2-oxoacetyl)oxepan-4-yl)-1-((R)-2-amino-3-cyclohexylpropanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide Hydrochloride (69)

The title compound was prepared in a similar manner to last step of Intermediate J using compound 67.

Steps 5: Preparation of (2S,4S)—N—((R or S)-4-(2-amino-2-oxoacetyl)oxepan-4-yl)-1-((R or S)-3-cyclohexyl-2-(4-((difluoromethyl)sulfonyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide

The title compound was prepared in a similar manner to Example 3 using compound 69 with a 1 hour reaction time. MS (ESI+): 780 (M+1)^(⊕)

The following compounds were prepared in a similar manner as Example 153 substituting 4-((difluoromethyl)sulfonyl)benzoic acid with other commercially available carboxylic acids.

Example Structure/Name MW MS (ESI+) Example 154

769.91 770 (M + 1)^(⊕) (2S,4S)-N-((R or S)-4-(2-amino-2-oxoacetyl)oxepan-4- yl)-1-((R)-3-cyclohexyl-2-(4- (cyclopropylsulfonyl)benzamido)propanoyl)-4-(5-(2- hydroxypropan-2-yl)-1H-1,2,3-triazol-1- yl)pyrrolidine-2-carboxamide Example 155

784.92 785 (M + 1)^(⊕) (2S,4S)-N-((R or S)-4-(2-amino-2-oxoacetyl)oxepan-4- yl)-1-((R)-3-cyclohexyl-2-(4-(N- cyclopropylsulfamoyl)benzamido)propanoyl)-4-(5-(2- hydroxypropan-2-yl)-1H-1,2,3-triazol-1- yl)pyrrolidine-2-carboxamide

Example 156: (2S,4R)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-4-hydroxypyrrolidine-2-carboxamide

Step 1: Preparation of methyl (2S,4R)-1-((R)-2-((tert-butoxycarbonyl)amino)-3-cyclohexylpropanoyl)-4-hydroxypyrrolidine-2-carboxylate (70)

To a suspension of (R)-2-((tert-butoxycarbonyl)amino)-3-cyclohexylpropanoic acid (Chem-Impex, IL, catalog/t 03553) (10.0 g, 36.9 mmol) and HATU (15.4 g, 40.6 mmol) in DCM (100 mL) was added methyl (2S,4R)-4-hydroxypyrrolidine-2-carboxylate (CombiBlocks, CA, catalog #OR-0651) (7.38 g, 40.6 mmol) and iPr₂EtN (9.7 mL, 55.4 mmol) and the reaction mixture was stirred at 23° C. After 18 hours, the reaction was quenched with water (100 mL) and sat. aq. NaHCO₃ (100 mL) and extracted with DCM (3×75 mL). The combined extracts were concentrated under reduced pressure. This residue was purified by column chromatography using RediSep cartridge (120 g, silica gel) eluting with a 20-100% EtOAc in hexanes gradient. The desired fractions were concentrated under reduced pressure to provide the title compound.

Step: 2: Preparation of methyl (2S,4R)-1-((R)-2-amino-3-cyclohexylpropanoyl)-4-hydroxypyrrolidine-2-carboxylate (71)

To a solution of compound 70 (10.6 g, 26.6 mmol) in MeOH (100 mL) was added 36% aq. HCl (3.0 mL) and heated to 50° C. After 18 hours, the mixture was concentrated under reduced pressure. The residual solvent was removed by azeotrope with toluene (3×20 mL) to provide the title compound.

Step 3: Preparation of methyl (2S,4R)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4-hydroxypyrrolidine-2-carboxylate (72)

To a yellow solution of compound 71 (26.6 mmol) and iPr₂EtN (9.3 mL, 53.2 mmol) in DCM (100 mL) was added pyridine (105 μL, 1.3 mmol) and 2-naphthoyl chloride (5.58 g, 29.3 mmol) and the reaction mixture was stirred at 23° C. After 2 h time, the reaction was quenched with water (100 mL) and extracted with DCM (3×75 mL). The combined extracts were washed with brine and concentrated under reduced pressure. The resulting brown solid was dissolved in DCM (50 mL) and cooled to 0° C. This solution was treated with hexanes (50 mL) added slowly to help induce crystallization. The suspension was cooled to −20° C. for 1 hour and then filtered and the solid was washed with hexanes (2×15 mL) to provide the title compound as a white solid.

Step 4: Preparation of (2S,4R)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4-hydroxypyrrolidine-2-carboxylic Acid (73)

The title compound was prepared in a similar manner to Intermediate I, Step 8, using compound 72 and stirring at room temperature for 3 h.

Steps 5-6: Preparation of (2S,4R)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-4-hydroxypyrrolidine-2-carboxamide

The title compound was prepared in a similar manner to Example 71 using compound 73 and Intermediate B. MS (ESI+): 593 (M+1)

In step 6, the reaction mixture was stirred for 18 hours at room temperature.

Example 157: (S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-4-oxopyrrolidine-2-carboxamide

The title compound was prepared in a similar manner as step 2 of Example 2 using (2S,4R)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-(4-(2-amino-1-hydroxy-2-oxoethyl)tetrahydro-2H-pyran-4-yl)-4-hydroxypyrrolidine-2-carboxamide and run at 23° C. for 18 hours. MS (ESI+): 591 (M+1)^(⊕)

Example 158: (2S,4R)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-4-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)pyrrolidine-2-carboxamide

To a suspension of (2S,4R)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-4-hydroxypyrrolidine-2-carboxamide (Example 156) (100 mg, 0.169 mmol), uracil (TCI, catalog #U0013) (44 mg, 0.389 mmol) and triphenylphosphine (102 mg, 0.389 mmol) in THF (1 mL) was added DIAD (76 μL, 0.389 mmol) and the reaction mixture was stirred at 23° C. After 1 hour, the mixture was loaded onto a C18 precartridge (5 g) and dried under vacuum. This material was purified by reverse phase chromatography using a C18 reverse phase RediSep cartridge (30 g) eluting with a 15-80% ACN in water gradient containing 0.1% formic acid. The desired fractions were concentrated under reduced pressure to provide the title compound as a white solid. MS (ESI+): 709 (M+Na)^(⊕)

The following compounds were prepared in a similar manner as Example 158 substituting uracil with other commercially available heterocyclic/heteroaromatic compounds.

Example Structure/Name MW MS (ESI+) Example 159

670.75 671 (M + 1)^(⊕) (2S,4S)-1-((R)-2-(2-naphthamido)-3- cyclohexylpropanoyl)-N-(4-(2-amino-2- oxoacetyl)tetrahydro-2H-pyran-4-yl)-4-(6- oxopyridazin-1(6H)-yl)pyrrolidine-2-carboxamide Example 160

709.79 710 (M + 1)^(⊕) (2S,4S)-1-((R)-2-(2-naphthamido)-3- cyclohexylpropanoyl)-N-(4-(2-amino-2- oxoacetyl)tetrahydro-2H-pyran-4-yl)-4-(3-oxo- [1,2,4]triazolo[4,3-α]pyridin-2(3H)- yl)pyrrolidine-2-carboxamide Example 161

721.8 744 (M + Na)^(⊕) (2S,4S)-1-((R)-2-(2-naphthamido)-3- cyclohexylpropanoyl)-N-(4-(2-amino-2- oxoacetyl)tetrahydro-2H-pyran-4-yl)-4-(1,3- dioxoisoindolin-2-yl)pyrrolidine-2-carboxamide Example 162

673.76 674 (M + 1)^(⊕) (2S,4S)-1-((R)-2-(2-naphthamido)-3- cyclohexylpropanoyl)-N-(4-(2-amino-2- oxoacetyl)tetrahydro-2H-pyran-4-yl)-4-((5- methylisoxazol-3-yl)oxy)pyrrolidine-2-carboxamide Example 163

705.2 727 (M + Na)^(⊕) (2S,4S)-1-((R)-2-(2-naphthamido)-3- cyclohexylpropanoyl)-N-(4-(2-amino-2- oxoacetyl)tetrahydro-2H-pyran-4-yl)-4-(3-chloro-6- oxopyridazin-1(6H)-yl)pyrrolidine-2-carboxamide Example 164

669.77 670 (M + 1)^(⊕) (2S,4S)-1-((R)-2-(2-naphthamido)-3- cyclohexylpropanoyl)-N-(4-(2-amino-2- oxoacetyl)tetrahydro-2H-pyran-4-yl)-4-(2-oxopyridin- 1(2H)-yl)pyrrolidine-2-carboxamide

Example 165: (4-((2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamido)tetrahydro-2H-pyran-4-yl)boronic Acid

Step 1: Preparation of 2-methyl-N-(tetrahydro-4H-pyran-4-ylidene)propane-2-sulfinamide (75)

Into a 100 mL round-bottom flask equipped with a magnetic stir bar and under nitrogen was added tetrahydropyran-4-one (Combi-Block, CA, catalog #AM-1010) (1.84 g, 18.4 mmol), 2-methyl-2-propanesulfinamide (2.25 g, 18.4 mmol), Ti(OiPr)₄ (8.1 mL, 37.0 mmol) and THF (anhydrous, 25 mL). The orange solution was refluxed for 2 hours. TLC (EtOAc:hexanes 1:1) analysis revealed completion of reaction. The mixture was cooled to 23° C. and quenched with sat. aq. NaHCO₃ (4 mL) and filtered through a pad of celite. The resulting yellow filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using a RediSep cartridge (50 g, silica gel) eluting with hexane:EtOAc (1:1). The desired fractions were concentrated under reduced pressure to provide the title product as a yellow oil.

Step 2: Preparation of 2-methyl-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)tetrahydro-2H-pyran-4-yl)propane-2-sulfinamide (76)

Into a 8 mL vial equipped with a magnetic stir bar and under nitrogen was added PCy₃.BF₄ (11 mg, 0.03 mmol), toluene (1.5 mL), water (300 μL) and CuSO₄ (5 mg, 0.03 mmol). The blue solution was treated with benzylamine (8 μL, 0.08 mmol) and the reaction mixture was stirred at 23° C. for 10 min. The mixture was treated with compound 75 (300 mg, 1.5 mmol) as a solution in toluene (1.0 mL), and bis(pinacolate)diboron (762 mg, 3.0 mmol). The resulting light brown solution was stirred at room temperature for 24 hours. LC-MS analysis revealed product formation. The reaction mixture was filtered through a plug of Fluorosil (5 cm×3 cm), eluting with EtOAc (3×15 mL). The filtrate was concentrated under reduced pressure to provide the title compound as an oil.

Step 3: Preparation of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)tetrahydro-2H-pyran-4-amine Hydrochloride (77)

Into a 100 mL round-bottom flask equipped with a magnetic stir bar and under nitrogen was added compound 76 (1.5 mmol), methanol (1 mL) and dioxane (3 mL). The yellow solution was treated with 4 M HCl in dioxane (3 mL, 0.75 mmol)) and stirred at 23° C. for 1 hour. The reaction mixture was concentrated under reduced pressure, resuspended in Et₂O (10 mL) and the mixture was stirred at 23° C. After 20 min, the suspension was filtered through a 0.45 μM Nylon filter washing with Et₂O (2×2 mL) to provide the title compound as a beige solid.

Step 4: Preparation of (2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)tetrahydro-2H-pyran-4-yl)pyrrolidine-2-carboxamide (78)

Into an 8 mL sample vial equipped with a magnetic stir bar and under nitrogen was added Intermediate I (64 mg, 0.12 mmol), compound 77 (92 mg, 0.35 mmol), PyAOP (75 mg, 0.14 mmol), DMF (1 mL) and EtN(iPr)₂ (61 μL, 0.35 mmol). The yellow suspension was stirred at 23° C. for 18 hours. LC-MS revealed approximately 40% product formation. The reaction was quenched with water (5 mL) and extracted with DCM (3×5 mL) using a Cl-phase separatory cartridge. The combined organics were concentrated under reduced pressure. This residue was purified by reverse phase column chromatography using a C18 RediSep Gold cartridge (30 g) eluting with 5% MeOH in DCM. The desired fractions were concentrated under reduced pressure and dried under high vacuum for 18 hours to afford the title compound as a white solid.

Step 5: Preparation of (4-((2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamido)tetrahydro-2H-pyran-4-yl)boronic Acid

Into a 5 mL sample vial equipped with a magnetic stir bar and under nitrogen was added compound 78 (14 mg, 0.019 mmol), isobutyl boronic acid (9 mg, 0.093 mmol) in methanol (1 mL) and hexanes (1 mL). The reaction mixture was treated with 1 M aq. HCl (76 μl, 0.076 mmol) and the biphasic suspension was stirred rigorously at room temperature for 4 hours. The top hexanes layer was further extracted with methanol (2×1 mL). The combined methanol layers were washed with hexanes (2×1 mL) and concentrated under reduced pressure to provide the title compound as a white solid. MS (ESI+): 657.7 (M+1-18)^(⊕)

While preferred embodiments of the present disclosure have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the present disclosure. It should be understood that various alternatives to the embodiments of the present disclosure described herein may be employed in practicing the present disclosure. It is intended that the following claims define the scope of the present disclosure and that methods and structures within the scope of these claims and their equivalents be covered thereby. 

What is claimed is:
 1. A compound of Formula (I):

or a pharmaceutically acceptable salt, solvate, solvate of the salt or prodrug thereof wherein: W is selected from the group consisting of: —B(OH)₂ and —C(O)C(O)NR⁷R⁸; X is selected from the group consisting of: —O—, —S(O)_(p)— and —N(C(O)OR⁶)—; Y is selected from the group consisting of: —C(O)—, —SO₂—, and —NHC(O)—; R¹ is selected from the group consisting of: (a) —(CH₂)₀₋₆-aryl, (b) —(CH₂)₀₋₆-heteroaryl, (c) —(CH₂)₀₋₆—C₃₋₈cycloalkyl optionally substituted with phenyl, and (d) —(CH₂)₀₋₆-heterocyclyl optionally substituted with phenyl or oxo, wherein the aryl and heteroaryl of choices (a) and (b) are each optionally substituted with 1 to 3 substituents independently selected from the group consisting of: (i) -halogen, (ii) —CN, (iii) —C₁₋₆alkyl, (iv) —C₀₋₆alkyl-R⁵, (v) —C₂₋₆alkenyl, (vi) —C₂₋₆alkynyl, (vii) —C(O)R⁷, (viii) —CO₂R⁷, (ix) —CONR⁷R⁸, (x) —OH, (xi) —O—C₁₋₆alkyl, (xii) —O—C₀₋₆alkyl-R⁵, (xiii) —SH, (xiv) —S(O)_(p)—C₁₋₆alkyl, (xv) —S(O)_(p)—C₀₋₆alkyl-R⁵, (xvi) —S(O)₂NR⁷R⁸, (xvii) —NO₂, (xviii) —NR⁷R⁸, (xix) —NHC(O)R⁷, (xx) —NHC(O)OR⁷, (xxi) —NHC(O)NR⁷R⁸, (xxii) —NHSO₂C₁₋₆alkyl, and (xxiii) —NHSO₂C₀₋₆alkyl-R⁵, wherein each of the alkyl group of choices (iii), (iv), (xi), (xii), (xiv), (xv), (xxii) and (xxiii) is optionally substituted with 1 to 5 substituents independently selected from -halogen, -haloC₁₋₄alkyl, —COR⁷, —CO₂R⁷, —CONR⁷R⁸, —NR⁷R⁸, —OH, —O—C₁₋₄alkyl, —SH and —S—C₁₋₄alkyl; R² is selected from the group consisting of: (a) —C₃₋₈alkyl and (b) —C₀₋₆alkyl-R⁵, wherein each of the alkyl group of choices (a) and (b) is optionally substituted with 1 to 5 substituents independently selected from: (i) -halogen, (ii) -haloC₁₋₄alkyl, (iii) —NR⁷R⁸, (iv) —OH, (v) —O—C₁₋₄alkyl, (vi) —SH, (vii) —S—C₁₋₄alkyl; (viii) —NR⁷SO₂C₁₋₄alkyl, and (ix) —NR⁷C(O)OR⁷, R^(3a) is H, and R^(3b) is selected from the group consisting of: (a) —H, (b) —OH, (c) -heteroaryl, (d) —O-heteroaryl, (e) -heterocycle, (f) -aryl, and (g) —O-aryl; wherein each of the heteroaryl of choices (c) and (d), the heterocycle of choice (e) and the aryl of choices (f) and (g) is optionally substituted with 1 to 3 groups independently selected from the group consisting of: (i) -halogen, (ii) —OH, (iii) —CR¹⁰R¹¹R¹², (iv) —(CH₂)₀₋₃—NHSO₂—C₁₋₄alkyl, (v) —(CH₂)₀₋₃—SO₂—C₁₋₄alkyl, (vi) —(CH₂)₀₋₃—C(O)O—C₁₋₄alkyl, and (vii) —CN; and wherein the heterocycle of choice (e) is additionally optionally substituted with 1 to 2 oxo groups; or R^(3a) and R^(3b) together represent oxo; each R⁴ is independently selected from the group consisting of: (a) —C₁₋₄alkyl, (b) -haloC₁₋₄alkyl, (c) —OH, (d) —O—C₁₋₄alkyl, (e) —O-haloC₁₋₄alkyl, and (f) -halogen; each R⁵ is independently selected from the group consisting of: (a) —C₃₋₁₂cycloalkyl, (b) -aryl, (c) -heteroaryl, and (d) -heterocyclyl, wherein each of choices (a) to (d) is optionally substituted with 1 to 3 substituents independently selected from the group consisting of: (i) —C₁₋₄alkyl, (ii) -halogen, (iii) —NR⁷R⁸, (iv) —OH, (v) —O—C₁₋₄alkyl, (vi) —SH, and (vii) —S—C₁₋₄alkyl; wherein each of the alkyl group of choices (i), (v) and (vii) is optionally substituted with 1 to 5 substituents independently selected from -halogen, -haloC₁₋₄alkyl, —OH, —O—C₁₋₄alkyl, —SH and —S—C₁₋₄alkyl; R⁶ is selected from the group consisting of: (a) —C₁₋₆alkyl, and (b) —C₀₋₆alkyl-aryl; each R⁷ and each R⁸ are independently selected from the group consisting of: (a) —H, (b) —C₁₋₆alkyl, (c) —C₀₋₆alkyl-C₃₋₁₂cycloalkyl, (d) —C₀₋₆alkyl-heterocyclyl, (e) —C₀₋₆alkyl-heteroaryl, (f) —C₀₋₆alkyl-aryl, (g) —C₂₋₆alkenyl, and (h) —C₂₋₆alkynyl, wherein the alkyl group of choices (b)-(f), the alkenyl group of choice (g), the cycloalkyl group of choice (c), and the alkynyl group of (h) is optionally substituted with 1 to 3 groups independently selected from: (i) -halogen, (ii) —C₁₋₄alkyl, (iii) —C(O)C₁₋₄alkyl, (iv) —OH, (v) —OC₁₋₄alkyl, (vi) —SH, (vii) —SC₁₋₄alkyl, (viii) —NH₂, (ix) —NH(C₁₋₄alkyl), and (x) —N(C₁₋₄alkyl)(C₁₋₄alkyl); or R⁷, R⁸ and the nitrogen atom to which they are attached together form a 3- to 7-membered monocyclic or 6- to 11-membered bicyclic heterocycle optionally having an additional heteroatom selected from O, S(O)_(p), and NR⁹, and wherein said heterocycle is optionally substituted with 1 to 2 groups independently selected from halogen; R⁹ is selected from the group consisting of: (a) —H, (b) —C₁₋₄alkyl, (c) —C(O)—C₁₋₄alkyl, (d) —C(O)NH₂, (e) —C(O)—NH(C₁₋₄alkyl), (f) —C(O)—N(C₁₋₄alkyl)₂, and (g) —C(O)O—C₁₋₄alkyl; R¹⁰, R¹¹, and R¹² are independently selected from the group consisting of: H, halogen, —OH and —C₁₋₆ alkyl; or R¹⁰, R¹¹ and the carbon atom to which they are attached together form a C₃₋₁₂cycloalkyl or a heterocyclyl group; k is 0, 1, 2, 3 or 4; n and m are independently selected from 0, 1, 2 and 3, with the proviso that n+m is 0, 1, 2, 3 or 4; and p is 0, 1 or
 2. 2. A compound of claim 1 wherein R¹ is selected from the group consisting of: (a) -aryl, and (b) -heteroaryl, wherein the aryl and heteroaryl of choices (a) and (b) are each optionally substituted with 1 to 3 substituents independently selected from the group consisting of: (i) -halogen, (ii) —CN, (iii) —C₁₋₆alkyl, (iv) —C₀₋₆alkyl-R⁵, (v) —C₂₋₆alkenyl, (vi) —C₂₋₆alkynyl, (vii) —C(O)R⁷, (viii) —CO₂R⁷, (ix) —CONR⁷R⁸, (x) —OH, (xi) —O—C₁₋₆alkyl, (xii) —O—C₀₋₆alkyl-R⁵, (xiii) —SH, (xiv) —S(O)_(p)—C₁₋₆alkyl, (xv) —S(O)_(p)—C₀₋₆alkyl-R⁵, (xvi) —S(O)₂NR⁷R⁸, (xvii) —NO₂, (xviii) —NR⁷R⁸, (xix) —NHC(O)R⁷, (xx) —NHC(O)OR⁷, (xxi) —NHC(O)NR⁷R⁸, (xxii) —NHSO₂C₁₋₆alkyl, and (xxiii) —NHSO₂C₀₋₆alkyl-R⁵, wherein each of the alkyl group of choices (iii), (iv), (xi), (xii), (xiv), (xv), (xxii) and (xxiii) is optionally substituted with 1 to 5 substituents independently selected from -halogen, -haloC₁₋₄alkyl, —COR⁷, —CO₂R⁷, —CONR⁷R⁸, —NR⁷R⁸, —OH, —O—C₁₋₄alkyl, —SH and —S—C₁₋₄alkyl.
 3. A compound of claim 1 or claim 2 wherein R^(3b) is selected from the group consisting of: (a) —OH, (b) -heteroaryl, (c) —O-heteroaryl, (d) -heterocycle, (e) -aryl, and (f) —O-aryl; wherein each of the heteroaryl of choices (b) and (c), the heterocycle of choice (d) and the aryl of choices (e) and (f) is optionally substituted with 1 to 3 groups independently selected from the group consisting of: (i) -halogen, (ii) —OH, (iii) —CR¹⁰R¹¹R¹², (iv) —C₀₋₃alkyl-NHSO₂—C₁₋₄alkyl, (v) —C₀₋₃alkyl-SO₂—C₁₋₄alkyl, (vi) —C₀₋₃alkyl-C(O)O—C₁₋₄alkyl, and (vii) —CN; wherein the heterocycle of choice (d) is additionally optionally substituted with 1 to 2 oxo groups; or R^(3a) and R^(3b) together represent oxo.
 4. A compound of any one of claims 1 through 3 wherein R^(3b) is selected from the group consisting of: (a) —OH, (b) -heteroaryl, (c) —O-heteroaryl, and (d) -heterocycle, wherein each of the heteroaryl of choices (b) and (c), and the heterocycle of choice (d) is optionally substituted with 1 to 3 groups independently selected from the group consisting of: (i) -halogen, (ii) —OH, (iii) —CR¹⁰R¹¹R¹², (iv) —C₀₋₃alkyl-NHSO₂—C₁₋₄alkyl, (v) —C₀₋₃alkyl-SO₂—C₁₋₄alkyl, (vi) —C₀₋₃alkyl-C(O)O—C₁₋₄alkyl, and (vii) —CN; wherein the heterocycle of choice (d) is additionally optionally substituted with 1 to 2 oxo groups.
 5. A compound of any one of claims 1 through 4 wherein R^(3b) is selected from the group consisting of: (a) —OH, (b)

(c) —O-heteroaryl, and (d)

wherein HAr is heteroaryl and Hcyl is heterocycle, and HAr, heteroaryl of choice (c), and Hcyl are each optionally substituted with 1 to 3 groups independently selected from the group consisting of: (i) -halogen, (ii) —OH, (iii) —CR¹⁰R¹¹R¹², (iv) —C₀₋₃alkyl-NHSO₂—C₁₋₄alkyl, (v) —C₀₋₃alkyl-SO₂—C₁₋₄alkyl, (vi) —C₀₋₃alkyl-C(O)O—C₁₋₄alkyl, and (vii) —CN; wherein Hcyl is additionally optionally substituted with 1 to 2 oxo groups.
 6. A compound of any one of claims 1 through 5 wherein R^(3b) is selected from the group consisting of: (a)

 and (b)

wherein HAr is heteroaryl and Hcyl is heterocycle, and HAr and Hcyl are each optionally substituted with 1 to 3 groups independently selected from the group consisting of: (i) -halogen, (ii) —OH, (iii) —CR¹⁰R¹¹R¹², (iv) —C₀₋₃alkyl-NHSO₂—C₁₋₄alkyl, (v) —C₀₋₃alkyl-SO₂—C₁₋₄alkyl, (vi) —C₀₋₃alkyl-C(O)O—C₁₋₄alkyl, and (vii) —CN; wherein Hcyl is additionally optionally substituted with 1 to 2 oxo groups.
 7. A compound of any of claims 1 through 6 wherein R² is —C₁₋₆alkyl-R⁵, wherein the alkyl group is optionally substituted with 1 to 3 substituents independently selected from: (i) -halogen, (ii) -haloC₁₋₄alkyl, (iii) —O—C₁₋₄alkyl, (iv) —S—C₁₋₄alkyl.
 8. A compound of any of claims 1 through 7 wherein R⁵ is —C₃₋₁₂cycloalkyl optionally substituted with 1 to 3 substituents independently selected from the group consisting of: (i) —C₁₋₄alkyl, (ii) -halogen, (iii) —O—C₁₋₄alkyl, (iv) —S—C₁₋₄alkyl; wherein each of the alkyl group of choices (i), (iii) and (iv) is optionally substituted with 1 to 5 substituents independently selected from -halogen, -haloC₁₋₄alkyl, —OH, —O—C₁₋₄alkyl, —SH and —S—C₁₋₄alkyl.
 9. A compound of any of claims 1-8 wherein W is —C(O)C(O)NR⁷R⁸.
 10. A compound of any of claims 1-9 wherein X is —O— or —S(O)_(p)—.
 11. A compound of claim 1 having the formula (Ia):

or a pharmaceutically acceptable salt, solvate, solvate of the salt or prodrug thereof wherein: W is selected from the group consisting of: —B(OH)₂ and —C(O)C(O)NR⁷R⁸; X is —O— or —S(O)_(p)—; Y is selected from the group consisting of: —C(O)—, —SO₂—, and —NHC(O)—; R¹ is selected from the group consisting of: (a) -aryl, (b) -heteroaryl, wherein the aryl and heteroaryl of choices (a) and (b) are each optionally substituted with 1 to 3 substituents independently selected from the group consisting of: (i) -halogen, (ii) —CN, (iii) —C₁₋₆alkyl, (iv) —C₀₋₆alkyl-R⁵, (v) —C₂₋₆alkenyl, (vi) —C₂₋₆alkynyl, (vii) —C(O)R⁷, (viii) —CO₂R⁷, (ix) —CONR⁷R⁸, (x) —OH, (xi) —O—C₁₋₆alkyl, (xii) —O—C₀₋₆alkyl-R⁵, (xiii) —SH, (xiv) —S(O)_(p)—C₁₋₆alkyl, (xv) —S(O)_(p)—C₀₋₆alkyl-R⁵, (xvi) —S(O)₂NR⁷R⁸, (xvii) —NO₂, (xviii) —NR⁷R⁸, (xix) —NHC(O)R⁷, (xx) —NHC(O)OR⁷, (xxi) —NHC(O)NR⁷R⁸, (xxii) —NHSO₂C₁₋₆alkyl, and (xxiii) —NHSO₂C₀₋₆alkyl-R⁵, wherein each of the alkyl group of choices (iii), (iv), (xi), (xii), (xiv), (xv), (xxii) and (xxiii) is optionally substituted with 1 to 5 substituents independently selected from -halogen, -haloC₁₋₄alkyl, —COR⁷, —CO₂R⁷, —CONR⁷R⁸, —NR⁷R⁸, —OH, —O—C₁₋₄alkyl, —SH and —S—C₁₋₄alkyl; R^(3a) is H and R^(3b) is selected from the group consisting of: (a) —OH, (b) -heteroaryl, (c) —O-heteroaryl, (d) -heterocycle, (e) -aryl, and (f) —O-aryl; wherein each of the heteroaryl of choices (b) and (c), the heterocycle of choice (d) and the aryl of choices (e) and (f) is optionally substituted with 1 to 3 groups independently selected from the group consisting of: (i) -halogen, (ii) —OH, (iii) —CR¹⁰R¹¹R¹², (iv) —C₀₋₃alkyl-NHSO₂—C₁₋₄alkyl, (v) —C₀₋₃alkyl-SO₂—C₁₋₄alkyl, (vi) —C₀₋₃alkyl-C(O)O—C₁₋₄alkyl, and (vii) —CN; wherein the heterocycle of choice (d) is additionally optionally substituted with 1 to 2 oxo groups; or R^(3a) and R^(3b) together represent oxo; R⁴ is selected from the group consisting of: (a) —C₁₋₄alkyl, (b) -haloC₁₋₄alkyl, (c) —OH, (d) —O—C₁₋₄alkyl, (e) —O-haloC₁₋₄alkyl, and (f) -halogen; R⁵ is —C₃₋₁₂cycloalkyl optionally substituted with 1 to 3 substituents independently selected from the group consisting of: (i) —C₁₋₄alkyl, (ii) -halogen, (iii) —O—C₁₋₄alkyl, (iv) —S—C₁₋₄alkyl; wherein each of the alkyl group of choices (i), (iii) and (iv) is optionally substituted with 1 to 5 substituents independently selected from -halogen, -haloC₁₋₄alkyl, —OH, —O—C₁₋₄alkyl, —SH and —S—C₁₋₄alkyl; each R⁷ and each R⁸ are independently selected from the group consisting of: (a) —H, (b) —C₁₋₆alkyl, (c) —C₀₋₆alkyl-C₃₋₁₂cycloalkyl, (d) —C₀₋₆alkyl-heterocyclyl, (e) —C₀₋₆alkyl-heteroaryl, (f) —C₀₋₆alkyl-aryl, (g) —C₂₋₆alkenyl, and (h) —C₂₋₆alkynyl, wherein the alkyl group of choices (b)-(f), the alkenyl group of choice (g), the cycloalkyl group of choice (c), and the alkynyl group of (h) is optionally substituted with 1 to 3 groups independently selected from: (i) -halogen, (ii) —C₁₋₄alkyl, (iii) —C(O)C₁₋₄alkyl, (iv) —OH, (v) —OC₁₋₄alkyl, (vi) —SH, (vii) —SC₁₋₄alkyl, (viii) —NH₂, (ix) —NH(C₁₋₄alkyl), and (x) —N(C₁₋₄alkyl)(C₁₋₄alkyl); or R⁷, R⁸ and the nitrogen atom to which they are attached together form a 3- to 7-membered monocyclic or 6- to 11-membered bicyclic heterocycle optionally having an additional heteroatom selected from O, S(O)_(p), and NR⁹, and wherein said heterocycle is optionally substituted with 1 to 2 groups independently selected from halogen; R⁹ is selected from the group consisting of: (a) —H, (b) —C₁₋₄alkyl, (c) —C(O)—C₁₋₄alkyl, (d) —C(O)NH₂, (e) —C(O)—NH(C₁₋₄alkyl), (f) —C(O)—N(C₁₋₄alkyl)₂, and (g) —C(O)O—C₁₋₄alkyl; R¹⁰, R¹¹, and R¹² are independently selected from the group consisting of: H, halogen, —OH and —C₁₋₆ alkyl; or R¹⁰, R¹¹ and the atom to which they are attached together form a C₃₋₁₂cycloalkyl or a heterocyclyl group; k is 0, 1, 2, 3 or 4; n and m are independently selected from 0, 1, 2 and 3, with the proviso that n+m is 0, 1, 2, 3 or 4; p is 0, 1 or
 2. 12. A compound of claim 11 wherein R^(3b) is selected from the group consisting of: (a) —OH, (b)

(c) —O-heteroaryl, and (d)

wherein HAr is heteroaryl and Hcyl is heterocycle, and HAr, heteroaryl of choice (c), and Hcyl are each optionally substituted with 1 to 3 groups independently selected from the group consisting of: (i) -halogen, (ii) —OH, (iii) —CR¹⁰R¹¹R¹², (iv) —C₀₋₃alkyl-NHSO₂—C₁₋₄alkyl, (v) —C₀₋₃alkyl-SO₂—C₁₋₄alkyl, (vi) —C₀₋₃alkyl-C(O)O—C₁₋₄alkyl, and (vii) —CN; wherein Hcyl is additionally optionally substituted with 1 to 2 oxo groups.
 13. A compound of claim 11 or 12 wherein R^(3b) is selected from the group consisting of: (a)

 and (b)

wherein HAr is heteroaryl and Hcyl is heterocycle, and HAr and Hcyl are each optionally substituted with 1 to 3 groups independently selected from the group consisting of: (i) -halogen, (ii) —OH, (iii) —CR¹⁰R¹¹R¹², (iv) —C₀₋₃alkyl-NHSO₂—C₁₋₄alkyl, (v) —C₀₋₃alkyl-SO₂—C₁₋₄alkyl, (vi) —C₀₋₃alkyl-C(O)O—C₁₋₄alkyl, and (vii) —CN; wherein Hcyl is additionally optionally substituted with 1 to 2 oxo groups.
 14. A compound of any of claims 11 through 13 wherein W is —C(O)C(O)NH₂.
 15. A compound of any of claims 11 through 14 wherein Y is —C(O)—.
 16. A compound of any one of claims 11 through 14 wherein W is —C(O)C(O)NH₂; Y is —C(O)—; and R^(3b) is selected from the group consisting of: (a)

 and (b)

wherein HAr is heteroaryl and Hcyl is heterocycle, and each heteroaryl and heterocycle is optionally substituted with 1 to 3 groups independently selected from the group consisting of: (i) -halogen, (ii) —OH, (iii) —CR¹⁰R¹¹R¹², (iv) —C₀₋₃alkyl-NHSO₂—C₁₋₄alkyl, (v) —C₀₋₃alkyl-SO₂—C₁₋₄alkyl, (vi) —C₀₋₃alkyl-C(O)O—C₁₋₄alkyl, and (vii) —CN; wherein the heterocycle is additionally substituted with 1 to 2 oxo groups.
 17. A compound of claim 1 having the formula (Ib):

or a pharmaceutically acceptable salt, solvate, solvate of the salt or prodrug thereof, wherein W is selected from the group consisting of: —B(OH)₂ and —C(O)C(O)NR⁷R⁸; X is selected from the group consisting of: —O—, —S(O)_(p)— and —N(C(O)OR⁶)—; Y is selected from the group consisting of: —C(O)—, —SO₂—, and —NHC(O)—; R¹ is selected from the group consisting of: (a) -aryl, (b) -heteroaryl, wherein the aryl and heteroaryl of choices (a) and (b) are each optionally substituted with 1 to 3 substituents independently selected from the group consisting of: (i) -halogen, (ii) —CN, (iii) —C₁₋₆alkyl, (iv) —C₀₋₆alkyl-R⁵, (v) —C₂₋₆alkenyl, (vi) —C₂₋₆alkynyl, (vii) —C(O)R⁷, (viii) —CO₂R⁷, (ix) —CONR⁷R⁸, (x) —OH, (xi) —O—C₁₋₆alkyl, (xii) —O—C₀₋₆alkyl-R⁵, (xiii) —SH, (xiv) —S(O)_(p)—C₁₋₆alkyl, (xv) —S(O)_(p)—C₀₋₆alkyl-R⁵, (xvi) —S(O)₂NR⁷R⁸, (xvii) —NO₂, (xviii) —NR⁷R⁸, (xix) —NHC(O)R⁷, (xx) —NHC(O)OR⁷, (xxi) —NHC(O)N⁷R⁸, (xxii) —NHSO₂C₁₋₆alkyl, and (xxiii) —NHSO₂C₀₋₆alkyl-R⁵, wherein each of the alkyl group of choices (iii), (iv), (xi), (xii), (xiv), (xv), (xxii) and (xxiii) is optionally substituted with 1 to 5 substituents independently selected from -halogen, -haloC₁₋₄alkyl, —COR⁷, —CO₂R⁷, —CONR⁷R⁸, —NR⁷R⁸, —OH, —O—C₁₋₄alkyl, —SH and —S—C₁₋₄alkyl; R² is selected from the group consisting of: (a) —C₃₋₈alkyl and (b) —C₀₋₆alkyl-R⁵, wherein each of the alkyl group of choices (a) and (b) is optionally substituted with 1 to 5 substituents independently selected from: (i) -halogen, (ii) -haloC₁₋₄alkyl, (iii) —NR²R⁸, (iv) —OH, (v) —O—C₁₋₄alkyl, (vi) —SH, (vii) —S—C₁₋₄alkyl; (viii) —NR⁷SO₂C₁₋₄alkyl, and (ix) —NR⁷C(O)OR⁷, R⁴ is selected from the group consisting of: (a) —C₁₋₄alkyl, (b) -haloC₁₋₄alkyl, (c) —OH, (d) —O—C₁₋₄alkyl, (e) —O-haloC₁₋₄alkyl, and (f) -halogen; R⁵ is selected from the group consisting of: (a) —C₃₋₁₂cycloalkyl, (b) -aryl, (c) -heteroaryl, and (d) -heterocyclyl, wherein each of choices (a) to (d) is optionally substituted with 1 to 3 substituents independently selected from the group consisting of: (i) —C₁₋₄alkyl, (ii) -halogen, (iii) —NR⁷R⁸, (iv) —OH, (v) —O—C₁₋₄alkyl, (vi) —SH, and (vii) —S—C₁₋₄alkyl; wherein each of the alkyl group of choices (i), (v) and (vii) is optionally substituted with 1 to 5 substituents independently selected from -halogen, -haloC₁₋₄alkyl, —OH, —O—C₁₋₄alkyl, —SH and —S—C₁₋₄alkyl; R⁶ is selected from the group consisting of: (a) —C₁₋₆alkyl, and (b) —C₀₋₆alkyl-aryl; each R⁷ and each R⁸ are independently selected from the group consisting of: (a) —H, (b) —C₁₋₆alkyl, (c) —C₀₋₆alkyl-C₃₋₁₂cycloalkyl, (d) —C₀₋₆alkyl-heterocyclyl, (e) —C₀₋₆alkyl-heteroaryl, (f) —C₀₋₆alkyl-aryl, (g) —C₂₋₆alkenyl, and (h) —C₂₋₆alkynyl, wherein the alkyl group of choices (b)-(f), the alkenyl group of choice (g), the cycloalkyl group of choice (c), and the alkynyl group of (h) is optionally substituted with 1 to 3 groups independently selected from: (i) -halogen, (ii) —C₁₋₄alkyl, (iii) —C(O)C₁₋₄alkyl, (iv) —OH, (v) —OC₁₋₄alkyl, (vi) —SH, (vii) —SC₁₋₄alkyl, (viii) —NH₂, (ix) —NH(C₁₋₄alkyl), and (x) —N(C₁₋₄alkyl)(C₁₋₄alkyl); or R⁷, R⁸ and the nitrogen atom to which they are attached together form a 3- to 7-membered monocyclic or 6- to 11-membered bicyclic heterocycle optionally having an additional heteroatom selected from O, S(O)_(p), and NR⁹, and wherein said heterocycle is optionally substituted with 1 to 2 groups independently selected from halogen; R⁹ is selected from the group consisting of: (a) —H, (b) —C₁₋₄alkyl, (c) —C(O)—C₁₋₄alkyl, (d) —C(O)NH₂, (e) —C(O)—NH(C₁₋₄alkyl), (f) —C(O)—N(C₁₋₄alkyl)₂, and (g) —C(O)O—C₁₋₄alkyl; R¹⁰, R¹¹, and R¹² are independently selected from the group consisting of: H, halogen, —OH and —C₁₋₆ alkyl; or R¹⁰, R¹¹ and the carbon atom to which they are attached together form a C₃₋₁₂cycloalkyl or a heterocyclyl group; k is 0, 1, 2, 3 or 4; n and m are independently selected from 0, 1, 2 and 3, with the proviso that n+m is 0, 1, 2, 3 or 4; p is 0, 1 or
 2. 18. A compound of claim 17 wherein R² is —C₁₋₃alkyl-R⁵, and R⁵ is —C₃₋₁₂cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from the group consisting of: (i) —C₁₋₄alkyl, (ii) -halogen, (iii) —O—C₁₋₄alkyl, (iv) —S—C₁₋₄alkyl; wherein each of the alkyl group of choices (i), (iii) and (iv) is optionally substituted with 1 to 5 substituents independently selected from -halogen, -haloC₁₋₄alkyl, —OH, —O—C₁₋₄alkyl, —SH and —S—C₁₋₄alkyl.
 19. A compound of any of claims 17 through 18 wherein W is —C(O)C(O)NH₂; X is —O— or —S(O)_(p)—; and Y is —C(O)—.
 20. A compound of any of claims 1 through 19 wherein R¹ is selected from the group consisting of: (e) phenyl, (f) naphthyl, (g) 5- or 6-membered monocyclic heteroaryl ring, said ring having a heteroatom selected from N, O and S, and optionally 1, 2 or 3 additional N atoms; and (h) 8-, 9-, or 10-membered fused bicyclic heteroaryl ring, said ring having a heteroatom selected from N, O and S, and optionally 1, 2 or 3 additional N atoms; wherein each of choices (a)-(d) is optionally substituted with 1 or 2 substituents independently selected from the group consisting of: (vi) -halogen, (vii) —CONR⁷R⁹, (viii) —S(O)_(p)—C₁₋₆alkyl, (ix) —S(O)_(p)—C₀₋₆alkyl-R⁵, (x) —S(O)₂NR⁷R⁸, wherein each of the alkyl group of choices (iii) and (iv) is optionally substituted with 1 to 5 substituents independently selected from -halogen, -haloC₁₋₄alkyl, —COR⁷, —CO₂R⁷, —CONR⁷R⁸, —NR⁷R⁸, —OH, —O—C₁₋₄alkyl, —SH and —S—C₁₋₄alkyl.
 21. A compound of any of claims 1 through 20 wherein n and m are each 1, and k is
 0. 22. A compound of claim 1 having the formula (Ic):

or a pharmaceutically acceptable salt, solvate, solvate of the salt or prodrug thereof, wherein X is O or S(O)_(n); R¹ is selected from the group consisting of: (i) phenyl, (j) naphthyl, (k) 5- or 6-membered monocyclic heteroaryl ring, said ring having a heteroatom selected from N, O and S, and optionally 1, 2 or 3 additional N atoms; and (l) 8-, 9-, or 10-membered fused bicyclic heteroaryl ring, said ring having a heteroatom selected from N, O and S, and optionally 1, 2 or 3 additional N atoms; wherein each of choices (a)-(d) is optionally substituted with 1 or 2 substituents independently selected from the group consisting of: (xi) -halogen, (xii) —CONR⁷R⁸, (xiii) —S(O)_(p)—C₁₋₆alkyl, (xiv) —S(O)_(p)—C₀₋₆alkyl-R⁵, (xv) —S(O)₂NR⁷R⁸, wherein each of the alkyl group of choices (iii) and (iv) is optionally substituted with 1 to 5 substituents independently selected from -halogen, -haloC₁₋₄alkyl, —COR⁷, —CO₂R⁷, —CONR⁷R⁸, —NR⁷R⁸, —OH, —O—C₁₋₄alkyl, —SH and —S—C₁₋₄alkyl.
 23. A compound of claim 22 wherein R¹ is selected from naphthyl, imidazo[1,2-a]pyridinyl, quinolinyl, indazolyl, benzotriazolyl, benzisoxazolyl, benzoxazolyl, benzthiazolyl, benzofuranyl, indolyl, benzimidazolyl, and isoquinolinone.
 24. A compound of claim 22 wherein R¹ is phenyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of: (vi) -halogen, (vii) —CONR⁷R⁸, (viii) —S(O)_(p)—C₁₋₆alkyl, (ix) —S(O)_(p)—C₀₋₆alkyl-R⁵, (x) —S(O)₂NR⁷R⁸, wherein each of the alkyl group of choices (iii) and (iv) is optionally substituted with 1 to 5 substituents independently selected from -halogen, -haloC₁₋₄alkyl, —COR⁷, —CO₂R⁷, —CONR⁷R⁸, —NR⁷R⁸, —OH, —O—C₁₋₄alkyl, —SH and —S—C₁₋₄alkyl.
 25. A compound of claim 1 selected from the group consisting of: tert-butyl 4-((2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamido)-4-(2-amino-2-oxoacetyl)piperidine-1-carboxylate; (2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-(methylsulfonyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-(piperidin-1-ylsulfonyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; N—((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)carbamoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidin-1-yl)-3-cyclohexyl-1-oxopropan-2-yl)imidazo[1,2-a]pyridine-6-carboxamide; (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-2-(4-cyanobenzamido)-3-cyclohexylpropanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; N—((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)carbamoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidin-1-yl)-3-cyclohexyl-1-oxopropan-2-yl)quinoline-3-carboxamide; N—((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)carbamoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidin-1-yl)-3-cyclohexyl-1-oxopropan-2-yl)-1H-indazole-7-carboxamide; (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-((2-methoxyethyl)sulfonyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-((difluoromethyl)sulfonyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-2-(4-((2-amino-2-oxoethyl)sulfonyl)benzamido)-3-cyclohexylpropanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyclohexyl-2-(6-methoxy-2-naphthamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyclohexyl-2-(1-methoxy-2-naphthamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyclohexyl-2-(6-(difluoromethoxy)-2-naphthamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyclohexyl-2-(6-(trifluoromethoxy)-2-naphthamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-(2-hydroxypropan-2-yl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-(2,2,2-trifluoro-1,1-dihydroxyethyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((2R)-3-cyclohexyl-2-(4-(2,2,2-trifluoro-1-hydroxyethyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; N—((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)carbamoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidin-1-yl)-3-cyclohexyl-1-oxopropan-2-yl)benzo[d]isoxazole-3-carboxamide; N—((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)carbamoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidin-1-yl)-3-cyclohexyl-1-oxopropan-2-yl)benzo[d]oxazole-2-carboxamide; N—((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)carbamoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidin-1-yl)-3-cyclohexyl-1-oxopropan-2-yl)benzo[d]thiazole-2-carboxamide; (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-2-(benzofuran-5-carboxamido)-3-cyclohexylpropanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; N—((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)carbamoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidin-1-yl)-3-cyclohexyl-1-oxopropan-2-yl)-1H-indole-6-carboxamide; N—((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)carbamoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidin-1-yl)-3-cyclohexyl-1-oxopropan-2-yl)-1H-indole-2-carboxamide; (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-fluorobenzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-(3-hydroxyoxetan-3-yl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-(isopropylsulfonyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-(cyclopropylsulfonyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; N—((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)carbamoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidin-1-yl)-3-cyclohexyl-1-oxopropan-2-yl)-1H-indazole-6-carboxamide; N—((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)carbamoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidin-1-yl)-3-cyclohexyl-1-oxopropan-2-yl)-1H-benzo[d][1,2,3]triazole-6-carboxamide; N—((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)carbamoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidin-1-yl)-3-cyclohexyl-1-oxopropan-2-yl)-1H-benzo[d]imidazole-2-carboxamide; N—((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)carbamoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidin-1-yl)-3-cyclohexyl-1-oxopropan-2-yl)-1H-benzo[d]imidazole-6-carboxamide; (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyclohexyl-2-(3-fluoro-4-(methylsulfonyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyclohexyl-2-(3-methyl-4-(methylsulfonyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-(cyclopentylsulfonyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-(ethylsulfonyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-((trifluoromethyl)sulfonyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-((2,2-difluoroethyl)sulfonyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-(N,N-dimethylsulfamoyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-sulfamoylbenzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-(N-cyclopropylsulfamoyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-(pyrrolidin-1-ylsulfonyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-(N,N-diethylsulfamoyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-(morpholinosulfonyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyclohexyl-2-(3-((difluoromethyl)sulfonyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyclohexyl-2-(2-((difluoromethyl)sulfonyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-2-(4-(cyclobutylsulfonyl)benzamido)-3-cyclohexylpropanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-2-(4-(N-cyclobutylsulfamoyl)benzamido)-3-cyclohexylpropanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-(N-(2,2,2-trifluoroethyl)sulfamoyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-(N-(prop-2-yn-1-yl)sulfamoyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-(N-(cyclopropylmethyl)sulfamoyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-(N-(2,2-difluoroethyl)sulfamoyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyclohexyl-2-(6-(oxetan-3-yloxy)-2-naphthamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyclohexyl-2-(6-(oxetan-3-yl)-2-naphthamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-(N-(3,3-difluorocyclobutyl)sulfamoyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyclohexyl-2-(3-phenylureido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyclohexyl-2-(3-(naphthalen-2-yl)ureido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyclohexyl-2-(3-(4-(trifluoromethyl)phenyl)ureido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyclohexyl-2-(3-(1-methyl-1H-indol-4-yl)ureido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-2-(3-(3-chloro-4-fluorophenyl)ureido)-3-cyclohexylpropanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyclohexyl-2-(3-cyclohexylureido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyclohexyl-2-(3-(naphthalen-1-yl)ureido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyclohexyl-2-(3-(4-phenyltetrahydro-2H-pyran-4-yl)ureido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-2-(3-benzylureido)-3-cyclohexylpropanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-2-(3-(4-cyanophenyl)ureido)-3-cyclohexylpropanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyclohexyl-2-(3-(4-(methylsulfonyl)phenyl)ureido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyclohexyl-2-(naphthalene-2-sulfonamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyclohexyl-2-(3,4-difluorophenylsulfonamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-(difluoromethoxy)phenylsulfonamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; (2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-(3-(2-amino-2-oxoacetyl)tetrahydrofuran-3-yl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; (2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-(4-(2-amino-2-oxoacetyl)oxepan-4-yl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; (2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N—((R)-4-(2-amino-2-oxoacetyl)oxepan-4-yl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; (2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N—((S)-4-(2-amino-2-oxoacetyl)oxepan-4-yl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; (2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-((difluoromethyl)sulfonyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-(methylsulfonyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; N—((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)carbamoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidin-1-yl)-3-cyclohexyl-1-oxopropan-2-yl)picolinamide; (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-(ethylsulfonyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; N—((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)carbamoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidin-1-yl)-3-cyclohexyl-1-oxopropan-2-yl)imidazo[1,2-a]pyridine-6-carboxamide; N—((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)carbamoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidin-1-yl)-3-cyclohexyl-1-oxopropan-2-yl)-1-oxo-1,2-dihydroisoquinoline-3-carboxamide; (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-(cyclopropylsulfonyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-(N-cyclopropylsulfamoyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; N—((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)carbamoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidin-1-yl)-3-cyclohexyl-1-oxopropan-2-yl)-2-methyl-2H-benzo[d][1,2,3]triazole-5-carboxamide; N—((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)carbamoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidin-1-yl)-3-cyclohexyl-1-oxopropan-2-yl)-1-methyl-1H-benzo[d][1,2,3]triazole-6-carboxamide; N—((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)carbamoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidin-1-yl)-3-cyclohexyl-1-oxopropan-2-yl)-1-methyl-1H-benzo[d][1,2,3]triazole-5-carboxamide; (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-((2-methoxyethyl)sulfonyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; N—((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)carbamoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidin-1-yl)-3-cyclohexyl-1-oxopropan-2-yl)-1H-benzo[d][1,2,3]triazole-5-carboxamide; N¹—((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)carbamoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidin-1-yl)-3-cyclohexyl-1-oxopropan-2-yl)terephthalamide; (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)-1-((R)-2-benzamido-3-cyclohexylpropanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; N—((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)carbamoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidin-1-yl)-3-cyclohexyl-1-oxopropan-2-yl)isonicotinamide; (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-(N-(prop-2-yn-1-yl)sulfamoyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H1-thiopyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-(N-(3,3-difluorocyclobutyl)sulfamoyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H1-thiopyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-(N-(oxetan-3-yl)sulfamoyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-(morpholinosulfonyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-(N-methylsulfamoyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-(N,N-dimethylsulfamoyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-(N-ethylsulfamoyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-(isopropylsulfonyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-((cyclopropylmethyl)sulfonyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-(N-(2,2-difluoroethyl)sulfamoyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; (2S,4S)-1-((R)-2-(4-((4-acetylpiperazin-1-yl)sulfonyl)benzamido)-3-cyclohexylpropanoyl)-N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-(pyrrolidine-1-carbonyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)-1-((R)-2-(4-(cyclobutylsulfonyl)benzamido)-3-cyclohexylpropanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; N¹—((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)carbamoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidin-1-yl)-3-cyclohexyl-1-oxopropan-2-yl)-N⁴,N⁴-dimethylterephthalamide; (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-(N-(1-methylcyclopropyl)sulfamoyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-((4-methylpiperazin-1-yl)sulfonyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)-1-((R)-2-(4-(azetidin-1-ylsulfonyl)benzamido)-3-cyclohexylpropanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-(pyrrolidin-1-ylsulfonyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-(N-(cyclopropylmethyl)sulfamoyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)-1-((R)-2-(4-(N-cyclobutylsulfamoyl)benzamido)-3-cyclohexylpropanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-(N-(2,2,2-trifluoroethyl)sulfamoyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-(N-(tetrahydro-2H-thiopyran-4-yl)sulfamoyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-((3,3-difluoroazetidin-1-yl)sulfonyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; (2S,4S)-1-((R)-2-(4-(2-oxa-6-azaspiro[3.3]heptan-6-ylsulfonyl)benzamido)-3-cyclohexylpropanoyl)-N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; (2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-(N-(3,3-dimethyl-2-oxobutyl)sulfamoyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; (2S,4S)—N-(4-(2-amino-2-oxoacetyl)-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-(pyrrolidin-1-ylsulfonyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; (2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-(4-(2-amino-2-oxoacetyl)-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; (2S,4S)—N-(4-(2-amino-2-oxoacetyl)-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-(methylsulfonyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; (2S,4S)—N-(4-(2-amino-2-oxoacetyl)-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-((difluoromethyl)sulfonyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; N—((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)carbamoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidin-1-yl)-3-cyclohexyl-1-oxopropan-2-yl)quinoline-3-carboxamide; N—((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)carbamoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidin-1-yl)-3-cyclohexyl-1-oxopropan-2-yl)-1H-indazole-7-carboxamide; (2S,4S)—N-(4-(2-amino-2-oxoacetyl)-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1-((R)-2-(4-cyanobenzamido)-3-cyclohexylpropanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; N—((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)carbamoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidin-1-yl)-3-cyclohexyl-1-oxopropan-2-yl)-1H-indazole-6-carboxamide; N¹—((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)carbamoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidin-1-yl)-3-cyclohexyl-1-oxopropan-2-yl)terephthalamide; (2S,4S)—N-(4-(2-amino-2-oxoacetyl)-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-nitrobenzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; (2S,4S)—N-(4-(2-amino-2-oxoacetyl)-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1-((R)-2-(4-bromobenzamido)-3-cyclohexylpropanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; (2S,4S)—N-(4-(2-amino-2-oxoacetyl)-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1-((R)-2-(4-chloro-2,5-difluorobenzamido)-3-cyclohexylpropanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; (2S,4S)—N-(4-(2-amino-2-oxoacetyl)-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1-((R)-3-cyclohexyl-2-(3,4-dichlorobenzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; N—((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)carbamoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidin-1-yl)-3-cyclohexyl-1-oxopropan-2-yl)-6-hydroxynicotinamide; N—((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)carbamoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidin-1-yl)-3-cyclohexyl-1-oxopropan-2-yl)-1-hydroxyisoquinoline-3-carboxamide; N—((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)carbamoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidin-1-yl)-3-cyclohexyl-1-oxopropan-2-yl)-7-fluoroquinoline-3-carboxamide; N—((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)carbamoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidin-1-yl)-3-cyclohexyl-1-oxopropan-2-yl)-7-chloroquinoline-3-carboxamide; (2S,4S)—N-(4-(2-amino-2-oxoacetyl)-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-(N-cyclopropylsulfamoyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; (2S,4S)—N-(4-(2-amino-2-oxoacetyl)-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1-((R)-2-(4-(N-cyclobutylsulfamoyl)benzamido)-3-cyclohexylpropanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; (2S,4S)—N-(4-(2-amino-2-oxoacetyl)-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-(N-(spiro[3.3]heptan-2-yl)sulfamoyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; (2S,4S)—N-(4-(2-amino-2-oxoacetyl)-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-(N-(2,2-difluoroethyl)sulfamoyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; (2S,4S)—N-(4-(2-amino-2-oxoacetyl)-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-(piperidin-1-ylsulfonyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; (2S,4S)—N-(4-(2-amino-2-oxoacetyl)-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1-((R)-2-(4-(N-(tert-butyl)sulfamoyl)benzamido)-3-cyclohexylpropanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; (2S,4S)—N-(4-(2-amino-2-oxoacetyl)-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-(N-phenylsulfamoyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; (2S,4S)—N-(4-(2-amino-2-oxoacetyl)-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-(N-cyclopropyl-N-methylsulfamoyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; (2S,4S)—N-(4-(2-amino-2-oxoacetyl)-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-(N-cyclopropyl-N-ethylsulfamoyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; (2S,4R)—N-(4-(2-amino-2-oxoacetyl)-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-(N-cyclopentylsulfamoyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; (2S,4S)—N-(4-(2-amino-2-oxoacetyl)-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-(N,N-dicyclopropylsulfamoyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; (2S,4S)—N-(4-(2-amino-2-oxoacetyl)-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1-((R)-3-cyclohexyl-2-(naphthalene-2-sulfonamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; (2S,4S)—N-(4-(2-amino-2-oxoacetyl)-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1-((R)-3-cyclohexyl-2-(3-(naphthalen-2-yl)ureido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; (2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-(4-(2-amino-2-oxoacetyl)-1-oxidotetrahydro-2H-thiopyran-4-yl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; (2S,4S)—N-(4-(2-amino-2-oxoacetyl)-1-oxidotetrahydro-2H-thiopyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-((difluoromethyl)sulfonyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; (2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-(3-(2-amino-2-oxoacetyl)tetrahydrothiophen-3-yl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; (2S,4R)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-(3-(2-amino-2-oxoacetyl)-1-oxidotetrahydrothiophen-3-yl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; (2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-(3-(2-amino-2-oxoacetyl)-1,1-dioxidotetrahydrothiophen-3-yl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; (2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-(3-(2-amino-2-oxoacetyl)-1,1-dioxidotetrahydro-2H-thiopyran-3-yl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; (2S,4S)—N—((R)-4-((2-amino-2-oxoacetyl)oxepan-4-yl)-1-((R)-3-cyclohexyl-2-(4-((difluoromethyl)sulfonyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; (2S,4S)—N—((S)-4-((2-amino-2-oxoacetyl)oxepan-4-yl)-1-((R)-3-cyclohexyl-2-(4-((difluoromethyl)sulfonyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; (2S,4S)—N—((R)-4-(2-amino-2-oxoacetyl)oxepan-4-yl)-1-((R)-3-cyclohexyl-2-(4-(cyclopropylsulfonyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; (2S,4S)—N—((S)-4-(2-amino-2-oxoacetyl)oxepan-4-yl)-1-((R)-3-cyclohexyl-2-(4-(cyclopropylsulfonyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; (2S,4S)—N—((R)-4-(2-amino-2-oxoacetyl)oxepan-4-yl)-1-((R)-3-cyclohexyl-2-(4-(N-cyclopropylsulfamoyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; (2S,4S)—N—((S)-4-(2-amino-2-oxoacetyl)oxepan-4-yl)-1-((R)-3-cyclohexyl-2-(4-(N-cyclopropylsulfamoyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; (2S,4R)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-4-hydroxypyrrolidine-2-carboxamide; (S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-4-oxopyrrolidine-2-carboxamide; (2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-4-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)pyrrolidine-2-carboxamide; (2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-4-(6-oxopyridazin-1(6H)-yl)pyrrolidine-2-carboxamide; (2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-4-(3-oxo-[1,2,4]triazolo[4,3-a]pyridin-2(3H)-yl)pyrrolidine-2-carboxamide; (2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-4-(1,3-dioxoisoindolin-2-yl)pyrrolidine-2-carboxamide; (2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-4-((5-methylisoxazol-3-yl)oxy)pyrrolidine-2-carboxamide; (2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-4-(3-chloro-6-oxopyridazin-1(6H)-yl)pyrrolidine-2-carboxamide; (2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-4-(2-oxopyridin-1(2H)-yl)pyrrolidine-2-carboxamide; and (4-((2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamido)tetrahydro-2H-pyran-4-yl)boronic acid; or a pharmaceutically acceptable salt, solvate, salt of the solvate, or prodrug thereof.
 26. A pharmaceutical composition comprising a compound of any one of claims 1-25 and a pharmaceutically acceptable carrier.
 27. A method of preventing, or treating a disease of the eye selected from dry-AMD, wet-AMD, geographic atrophy, diabetic retinopathy, retinopathy of prematurity, polypoidal choroidal vasculopathy, and degeneration of retinal or photoreceptor cells, comprising: administering to a subject in need thereof a therapeutically effective amount of a compound according to claim 1-25 or a pharmaceutically acceptable salt, solvate, solvate of the salt or prodrug thereof, or the pharmaceutical composition of claim
 26. 28. The method of preventing a disease of the eye, according to claim 27 wherein the method of prevention is selected from delaying the onset of disease and reducing the risk of developing a disease of the eye, wherein the disease of the eye is selected from dry-AMD, wet-AMD, geographic atrophy, diabetic retinopathy, retinopathy of prematurity, polypoidal choroidal vasculopathy, and degeneration of retinal or photoreceptor cells.
 29. The method of treating a disease of the eye according to claim 27 wherein the method is selected from controlling, alleviating, and slowing the progression of, wherein the disease is selected from dry-AMD, wet-AMD, geographic atrophy, diabetic retinopathy, retinopathy of prematurity, polypoidal choroidal vasculopathy, and degeneration of retinal or photoreceptor cells.
 30. The method according to any of claims 27 to 29 wherein the disease is geographic atrophy.
 31. A method of inhibiting HTRA1 protease activity in an eye comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to claims 1-25 or a pharmaceutically acceptable salt, solvate, solvate of the salt or prodrug thereof, or the pharmaceutical composition of claim
 26. 